ARTICLE | doi:10.20944/preprints202209.0359.v1
Subject: Mathematics & Computer Science, Applied Mathematics Keywords: Hematological malignancies; treatment outcomes; CAR-T cell exhaustion; memory 22 pool, functional CAR-T cells; antigen dependent CAR-T expansion
Online: 23 September 2022 (05:33:24 CEST)
Chimeric Antigen Receptor (CAR)-T cell immunotherapy revolutionized cancer treatment and consists of the genetic modification of T lymphocytes with a CAR gene, aiming to increase their ability to recognize and kill antigen-specific tumor cells. The dynamics of CAR-T cell responses in patients presents a multiphasic kinetics with distribution, expansion, contraction, and persistence phases. The characteristics and duration of each phase depend on the tumor type, the infused product, and on patient-specific characteristics. We present a mathematical model which describes the multiphasic CAR-T cell dynamics resulting from the interplay between CAR-T and tumor cells, considering patient and product heterogeneities. The CAR-T cell population is divided into functional (distributed and effector), memory, and exhausted CAR-T cell phenotypes. The model is able to describe the diversity of CAR-T cell dynamic behaviors in different patients and hematological cancers as well as their therapy outcomes. Our results indicate that the joint assessment of the area under the concentration-time curve in the first 28 days and the corresponding fraction of non-exhausted CAR-T cells may be considered as potential markers to classify therapy responses. Overall, the analysis of different CAR-T cell phenotypes can be a key aspect for a better understanding of the whole CAR-T cell dynamics.
REVIEW | doi:10.20944/preprints202008.0728.v1
Subject: Biology, Physiology Keywords: T cell exhaustion; chronic viral infections; cancer; immunotherapy; epigenetics; PD-1; inhibitory receptors
Online: 31 August 2020 (17:49:37 CEST)
T cells follow a triphasic distinct pathway of activation, proliferation and differentiation before becoming functionally and phenotypically ‘exhausted’ in settings of chronic infection, autoimmunity and in cancer. Exhausted T cells progressively lose canonical effector functions, exhibit altered transcriptional networks and epigenetic signatures and gain constitutive expression of a broad coinhibitory receptor suite. This review outlines recent advances in our understanding of exhausted T cell biology and examines cellular and molecular mechanisms by which a state of dysfunction or exhaustion is established, and mechanisms by which exhausted T cells may still contribute to pathogen or tumour control. Further, this review describes our understanding of exhausted T cell heterogeneity and outlines the mechanisms by which checkpoint blockade differentially engages exhausted T cell subsets to overcome exhaustion and recover T cell function.
REVIEW | doi:10.20944/preprints202109.0212.v1
Subject: Life Sciences, Other Keywords: BCMA; CAR T cell; Multiple Myeloma; Refractory/Relapsed; ADCs; Bispecific Antibody
Online: 13 September 2021 (12:36:12 CEST)
Multiple Myeloma (MM) is one of the incurable types of cancer in plasma cells. While immense progress has been made in the treatment of this malignancy, a large percentage of patients were unable to adapt to such therapy. Additionally, these therapies might be associated with significant diseases and are not always tolerated well in all patients. Since cancer in plasma cells has no cure, patients develop resistance to treatments, resulting in R/R MM. BCMA is primarily produced on mature B cells. Its up-regulation and activation are associated with multiple myeloma in both murine and human models, indicating that this might be an effective therapeutic target for this type of malignancy. Additionally, BCMA's predictive value, association with effective clinical trials, and capacity to be utilized in previously difficult to observe patient populations, imply that it might be used as a biomarker for multiple myeloma. Numerous kinds of BCMA-targeting medicines have demonstrated antimyeloma efficacy in individuals with refractory/relapsed MM, including CAR T-cell treatments, ADCs, bispecific antibody constructs. Among these medications, CART cell-mediated BCMA therapy has shown significant outcomes in multiple myeloma clinical trials. This review article outlines CAR T cell mediated BCMA medicines have the efficiency to change the therapeutic pattern for multiple myeloma significantly.
REVIEW | doi:10.20944/preprints201811.0525.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: immuno-oncology; CAR T-cell; lymphoma; one health
Online: 21 November 2018 (11:34:58 CET)
The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T-cells for targeted cancer therapy. CAR T-cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T-cell therapies were approved by the U. S Food and Drug Administration; one for the treatment of pediatric Acute Lymphoblastic Leukemia (ALL), the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T-cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B-cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin’s lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T-cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This Commentary summarizes the current state of knowledge on CAR T-cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.
ARTICLE | doi:10.20944/preprints202105.0323.v1
Subject: Mathematics & Computer Science, Applied Mathematics Keywords: CAR T; Bone Marrow; Mathematical Model; Acute Lymphoblastic Leukemia; B cell
Online: 14 May 2021 (11:26:20 CEST)
Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells and CAR T cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T cells and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load and tumor burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.
REVIEW | doi:10.20944/preprints202104.0517.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: CAR T-cells; chimeric antigen receptor T cells; cytokine release syndrome; central nervous system toxicity; neurotoxicity; adverse events; pathophysiology
Online: 19 April 2021 (21:17:34 CEST)
Anti-CD19 chimeric antigen receptor (CAR) T-cells represent a novel immunotherapy that has shown remarkable success in the treatment of adult relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma, adult R/R mantle cell lymphoma, and R/R acute paediatric lymphoblastic leukaemia. One barrier to the widespread use of CAR T-cell therapy is toxicity, primarily cytokine release syndrome (CRS) with a variable grade of severity. The main manifestations of CRS are fever, hypotension, cytopenia, organ dysfunction among others. Neurological toxicities vary widely and range from headaches to encephalopathy. In addition, anti-CD19 CAR T-cell therapy provokes an array of less frequent events, such as coagulopathies, delayed cytopenia, and cardiovascular toxicities. In general, toxicities are usually reversible and resolve on their own in most cases, though severe cases may require intensive care and immunosuppressive therapy. Deaths due to CRS, neurologic toxicity and infectious complications have been reported, which highlights the gravity of these syndromes and the critical nature of appropriate intervention. In this paper, we look at all available FDA- and EMA-approved information about the pathophysiology, clinical manifestations, risk factor reviews of existing toxicity grading systems, current management strategies, and guidelines for anti-CD19 CAR T-cell toxicities. We also present new approaches, which are under investigation, to mitigate these adverse events.
ARTICLE | doi:10.20944/preprints202109.0300.v1
Subject: Mathematics & Computer Science, Applied Mathematics Keywords: CAR T; Targeted Radionuclide Therapy; TRT; Mathematical Model; Multiple Myeloma; Immunotherapy; Daratumumab; CS1; Combination Therapy
Online: 17 September 2021 (09:32:33 CEST)
Targeted radionuclide therapy (TRT) has recently seen a surge in popularity, with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results – an example being chimeric antigen receptor (CAR) T-cells therapy in hematologic malignancies. Moreover, TRT and CAR T therapies possess unique features that require special consideration when determining how to dose, time, and sequence combination treatments, including the distribution of TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate additive or synergistic effects of combination therapies and warrant a mathematical treatment which includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here we combine two previously published mathematical models in a multiple myeloma setting to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell based therapies. We find that for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR T therapies.
ARTICLE | doi:10.20944/preprints202103.0625.v1
Subject: Life Sciences, Biochemistry Keywords: three population mathematical model; CAR-T lymphocytes; memory CAR-T cells; long-term immunity; tumor-induced immunosupression
Online: 25 March 2021 (14:39:02 CET)
Immunotherapy has gained great momentum with chimeric antigen receptor T cell (CAR-T) therapy, in which patient’s T lymphocytes are genetically manipulated to recognize tumor-specific antigens increasing tumor elimination efficiency. In the last years, CAR-T cell immunotherapy for hematological malignancies achieved a great response rate on patients and is a very promising therapy for several other malignancies. Each new CAR design requires a preclinical proof-of-concept experiment using immunodeficient mouse models. The absence of a functional immune system in these mice makes them simple and suitable to be mathematically modeled. In this work, we developed a three population mathematical model to describe tumor response to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for several phenomena, such as tumor-induced immunosuppression, memory pool formation, and conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual donor and tumor specificities were considered as uncertainties in the model parameters. Our model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly depends on some specific parameters such as the differentiation of effector to memory CAR-T cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In summary, our model can contribute to reduce and optimize the number of in vivo experiments with in silico tests to select specific scenarios that could be tested in experimental research. Such in silico laboratory was made available in a Shiny R-based platform called CARTmath. It is an open-source, easy to run simulator, available at github.com/tmglncc/CARTmath or directly on the webpage cartmath.lncc.br, containing this manuscript results as examples and documentation. The developed model, together with the CARTmath platform, provides potential use for assessing different CAR-T cell immunotherapy protocols and associated efficacy, becoming an accessory towards in silico trials.
REVIEW | doi:10.20944/preprints202201.0137.v1
Subject: Life Sciences, Immunology Keywords: Adoptive T cell therapy; CAR T cells; CRISPR/Cas9; gene modifications; T cells
Online: 11 January 2022 (12:57:40 CET)
Adaptive T cell immunotherapy holds great promise for the successful treatment of leukemia as well as other types of cancers. More recently, it was also shown to be an effective treatment option for chronic virus infections in immunosuppressed patients. Autologous or allogeneic T cells used for immunotherapy are usually genetically modified to express novel T cell or chimeric antigen receptors. The production of such cells was significantly simplified with the CRISPR/Cas system allowing deletion or insertion of novel genes at specific locations within the genome. In this review, we describe recent methodological breakthroughs important for the conduction of these genetic modifications, summarize crucial points to be considered when conducting such experiments, and highlight the potential pitfalls of these approaches.
REVIEW | doi:10.20944/preprints202010.0652.v1
Subject: Medicine & Pharmacology, Allergology Keywords: CAR T cells; immunotherapy; pediatric neuroblastoma; strategy
Online: 30 October 2020 (16:00:41 CET)
Chimeric antigen receptors (CARs) is one of the curative immunotherapeutic approaches that exploit the antigen specificity and cytotoxicity function of potent immune cells against cancers. Neuroblastoma, the most common extracranial pediatric solid tumors with diverse comportment, could be a promising candidate for using CARs therapies. Several methods harness CARs modified cells in neuroblastoma to increase therapeutic efficiency, albeit the assessment has still been less successful. Regarding the improvement of CARs, various trials have been launched to overcome insufficient capacity. However, the reason behind the inadequate response against neuroblastoma of CARs modified cells are still not well understood. It is essential to update the present reveal of comprehension of CARs to improve the efficiency of CARs therapies. This review summarizes the crucial features of CARs and its design for neuroblastoma, discusses challenges that impact the outcomes of the immunotherapeutic competence, and focuses on devising strategies currently investigated to improve the efficacy of CARs for neuroblastoma immunotherapy.
ARTICLE | doi:10.20944/preprints202007.0520.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Cancer immunotherapy; Prostate Cancer; CAR-T; PSMA
Online: 22 July 2020 (11:16:04 CEST)
Despite advances in the understanding of its molecular pathophysiology, prostate cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate specific membrane antigen (PSMA), a glycoprotein that is overexpressed in prostate cancer, which expression involves neovasculature of several tumor entities, thus envisaging an additional antiangiogenic effect. To optimize the CAR design, we compared two CARs with signaling domains containing one or two T cell costimulatory elements, in addition to CD3ζ. Conversely, what has been described for other CARs, a third-generation CAR (containing CD28 and 41BB co-signaling domains) induced a potent antitumor effect similar to a second-generation CAR (containing CD28 co-signaling domain), though we observed a detrimental effect of the additional costimulatory domain that was attributed to increased activation-induced cell death (AICD). This “super-stimulation” resulted in exhaustion of cells, higher frequencies of cell death and, more importantly, the impossibility of sufficiently expanding the CAR cells to obtain the minimum number of cells requested for in vivo therapies. While the superiority of 2nd and 3rd generation over 1st generation CAR T cells has been clearly shown in both preclinical and clinical studies, the optimal combination of costimulatory domains for 3rd generation CAR-T cells must still be defined and should be evaluated case-by-case in order to fine-tune immunotherapy approaches.
REVIEW | doi:10.20944/preprints202107.0198.v1
Subject: Medicine & Pharmacology, Allergology Keywords: CAR-T; TCR; cancer immunotherapy; immunotherapy clinical trials
Online: 8 July 2021 (11:04:10 CEST)
Chimeric antigen receptor and T-cell receptor (CAR-T/TCR) cellular immunotherapies have shown remarkable success in the treatment of some refractory B-cell malignancies, with potential to provide durable clinical response for other types of cancer. In this paper, we look at all available FDA CAR-T/TCR clinical trials for the treatment of cancer, and analyze them with respect to different disease tissues, targeted antigens, products, and originator locations. We found that 627 of 1,007 registered are currently active and of those 273 (44%) originated in China and 280 (45%) in the US. Our analysis suggests that the rapid increase in the number of clinical trials is driven by the development of different CAR-T products that use a similar therapeutic approach. We coin the term bioparallels to describe such products. Our results suggest that one feature of the CAR-T/TCR industry may be a robust response to success and failure of competitor products.
REVIEW | doi:10.20944/preprints202202.0022.v1
Subject: Life Sciences, Immunology Keywords: exosomes; T lymphocytes; immune synapse; secretory granules; multivesicular bodies; cytotoxic activity; cell death; CAR T lymphocytes
Online: 1 February 2022 (21:33:57 CET)
Extracellular vesicles (EV) are a very heterogeneous group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular communication, both locally and systemically, since they induce signals and transfer their contents (proteins, lipids, RNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. How-ever, cell surface receptor-induced EV release is limited to cells from the immune system, includ-ing T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptor for antigen and several bioactive molecules, including proapoptotic proteins. These EV are thus specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we discuss the generation of EV by T lymphocytes and some potential therapeutic approaches of these EV.
ARTICLE | doi:10.20944/preprints202204.0308.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: adoptive T cell therapy; hypoxic tumors; immune checkpoint blockade; CAR T; solid tumors; T cell exhaustion; co-stimulatory domains; CD28; 4-1BB; CD137
Online: 29 April 2022 (15:14:06 CEST)
The complete regression of clear cell renal cell carcinoma (ccRCC) obtained pre-clinically with anti-carbonic anhydrase IX (CAIX) G36 chimeric antigen receptor (CAR) T cells in doses equivalent to 10e8 CAR T cells/ Kg renewed the potential of this target to treat ccRCC and other tumors in hypoxia. The immune checkpoint blockade (ICB) brought durable clinical responses in advanced ccRCC and other tumors. Here we tested CD8/4-1BB compared to CD28-based anti-CAIX CAR PBMCs cells-releasing anti-programmed cell death ligand-1 (PD-L1) IgG4 for human ccRCC treatment in vitro and in an orthotopic NSG mice model in vivo. Using a 10e7 CAR PBMCs cells/ Kg dose, anti-CAIX CD28 CAR T cells releasing anti-PD-L1 IgG highly decrease both tumor volume and weight in vivo, avoiding the occurrence of metastasis. This antitumoral superiority of CD28-based CAR PBMCs cells compared to 4-1BB occurred under ICB via PD-L1. Furthermore, T cell exhaustion status in peripheral CD4 T cells, additionally to CD8 was critical for CAR T cells efficiency. The lack of hepatotoxicity and nephrotoxicity upon administration of 10e7 CAR PMBCs cells/Kg dose is the basis for carrying out clinical trials using anti-CAIX CD28 CAR PBMCs cells releasing anti-PD-L1 antibodies or anti-CAIX 4-1BB CAR T cells, offering exciting new prospects for the treatment of refractory ccRCC and hypoxic tumors.
REVIEW | doi:10.20944/preprints202009.0301.v1
Subject: Life Sciences, Immunology Keywords: Atherosclerosis; Phospholipases; Macrophages; T cells; Lipins
Online: 13 September 2020 (23:45:55 CEST)
Phospholipases are a family of lipid altering enzymes that can either reduce or increase bioactive lipid levels. Bioactive lipids elicit signaling responses, activate transcription factors, promote g-coupled protein activity, and modulate membrane fluidity that mediate cellular function. Phospholipases and the bioactive lipids they produce are important regulators on immune cell activity, dictating both pro-inflammatory and pro-resolving activity. During atherosclerosis, pro-inflammatory and pro-resolving activities govern atherosclerosis progression and regression respectively. This review will look at the interface of phospholipase activity, immune cell function, and atherosclerosis.
ARTICLE | doi:10.20944/preprints202012.0166.v1
Subject: Mathematics & Computer Science, Algebra & Number Theory Keywords: Mathematical oncology; CAR-T cells; mathematical immunology; mathematical modelling; immunotherapy of solid tumours; glioblastoma
Online: 7 December 2020 (15:06:37 CET)
Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial successes against B-cell malignancies, what has led to a growing scientific and clinical interest on extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immuno-suppressive tumour microenvironment, that is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, accounting for their immunosuppressive capabilities. Using the mathematical model, we show that the use of large numbers of CAR-T cells targeting the solid tumour antigens could overcome the cancer immunosuppressive potential. To achieve such high levels of CAR-T cells we propose and study computationaly, the manufacture and injection of CAR-T cells targeting two antigens: CD19 and a tumour-associated antigen. We study in-silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive generation of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its inmune suppression capabilities. That strategy could benefit from the combination with PD-1 inhibitors and of low tumour loads. Our computational results provide a theoretical support for the treatment of different types of solid tumours using T-cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD1 drugs after completion of classical cytoreductive treatments.
ARTICLE | doi:10.20944/preprints202005.0259.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cancer immunotherapy; prostate cancer; CAR; PSMA; NK-92 cell line
Online: 15 May 2020 (17:39:20 CEST)
Prostate cancer (PCa) has become the most common tumor among males in Europe and the USA. Adoptive immunotherapy appears as a promising strategy to control the advanced stages of the disease by specific targeting the tumor, in particular through chimeric antigen receptor T (CAR-T) cell therapy. Despite the advancements of CAR-T technology in the treatment of hematological malignancies, solid tumors still represent a challenge. To overcome current limits, other cellular effectors than T lymphocytes are under study as possible candidates for CAR-engineered cancer immunotherapy. A novel approach involves the NK-92 cell line, which mediates strong cytotoxic responses against a variety of tumor cells but has no effect on non-malignant healthy counterparts. Here, we report a therapeutic approach against PCa based on engineering of NK-92 cells with a CAR recognizing the human prostate-specific membrane antigen (PSMA), which is overexpressed in prostatic neoplastic cells. Upon CAR transduction, NK-92/CAR cells acquired high and specific lytic activity against PSMA-expressing prostate cancer cells in vitro, and also underwent degranulation and produced high levels of IFN-γ in response to antigen recognition. Lethal irradiation of the effectors, a safety measure requested for the clinical application of retargeted NK-92 cells, fully abrogated replication but did not impact on phenotype and short-term functionality. PSMA-specific recognition and antitumor activity were retained in vivo, as adoptive transfer of irradiated NK-92/CAR cells in prostate cancer-bearing mice restrained tumor growth and improved survival. Anti-PSMA CAR-modified NK-92 cells represent a universal, off-the-shelf, renewable and cost-effective product endowed with relevant potentialities as a therapeutic approach for PCa immunotherapy.
REVIEW | doi:10.20944/preprints202011.0016.v1
Subject: Life Sciences, Biochemistry Keywords: mast cells; adaptive immunity; dendritic cells; T cells
Online: 2 November 2020 (10:27:12 CET)
Although Mast cells are known as key drivers of type I allergic reactions, there is increasing evidence for their critical role in host defense. MCs do not only play an important role in initiating innate immune responses, but also influence the onset, kinetic and amplitude of the adaptive arm of immunity, or fine-tune the mode of the adaptive reaction. Intriguingly, MCs have been shown to affect T cell activation by direct interaction or indirectly by modifying properties of antigen-presenting cells, and can even modulate lymph node-borne adaptive responses remotely from the periphery. In this review, we provide a summary of recent findings that explain how MCs act as a link between the innate and the adaptive immunity, all the way from sensing inflammatory insult to orchestrating the final outcome of the immune response.
ARTICLE | doi:10.20944/preprints202108.0002.v1
Online: 2 August 2021 (08:43:20 CEST)
Human Rhinovirus (HRV) is the most common cause of upper respiratory infections and exacerbations of asthma. In this work, we selected 14 peptides (6 from HRV A and 8 from HRV C) encompassing potential CD4 T cell epitopes. Peptides were selected for being highly conserved in HRV A and C serotypes and predicted to bind to multiple HLA II molecules. We found positive T cell recall responses by IFNγ-ELISPOT assays to 8 peptides, validating 7 of them (3 from HRV A and 4 from HRV C) as CD4 T cell epitopes through intracellular cytokine staining assays. Additionally, we verified their promiscuous binding to multiple HLA II molecules by quantitative binding assays. According to their experimental HLA II binding profile, the combination of all these 7 epitopes could be presented and recognized by > 95 % of the world population. We actually determined IFNγ responses to a pool encompassing these CD4 T cell epitopes by intracellular cytokine staining, finding positive responses in 29 out of 30 donors. The CD4 T cell epitopes identified in this study could be key to monitor HRV infections and to develop peptide-based vaccines against most HRV A and C serotypes.
REVIEW | doi:10.20944/preprints202007.0139.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: Natural killer cells; NK cells; adoptive cell transfer; NK-92; CAR-NK; haNK; t-haNK
Online: 7 July 2020 (17:44:06 CEST)
Cellular therapy has emerged as an attractive option for the treatment of cancer, and adoptive transfer of chimeric antigen receptor (CAR) expressing T cells has gained FDA approval in hematologic malignancy. However, limited efficacy has been observed utilizing CAR-T therapy in solid tumors. Natural killer (NK) cells are crucial for tumor surveillance and exhibit potent killing capacity of aberrant cells in an antigen-independent manner. Adoptive transfer of unmodified allogeneic or autologous NK cells has shown limited clinical benefit due to factors including low cell number, low cytotoxicity and failure to migrate to tumor sites. To address these problems, immortalized and autologous NK cells have been genetically engineered to express high affinity receptors (CD16), CARs directed against surface proteins (PD-L1, CD19, Her2, etc.) and endogenous cytokines (IL-2 and IL-15) that are crucial for NK cell survival and cytotoxicity, with positive outcomes reported by several groups both preclinically and clinically. With a multitude of NK cell-based therapies currently in clinic trials, it is likely they will play a crucial role in next-generation cell therapy-based treatment. In this review we will highlight the recent advances and limitations of allogeneic, autologous and genetically enhanced NK cells used in adoptive cell therapy.
ARTICLE | doi:10.20944/preprints201904.0086.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Cryptococcal meningitis; Cryptococcus; HIV; CD4 T cells; CD8 T cells; adaptive immune response; IRIS
Online: 8 April 2019 (11:02:55 CEST)
Cryptococcal meningitis remains a significant opportunistic infection among HIV-infected patients, contributing 15%-20% of HIV-related mortality. A complication of initiating Antiretroviral therapy (ART) following opportunistic infection is Immune Reconstitution Inflammatory Syndrome (IRIS). IRIS afflicts 10-30% of HIV-infected patients with cryptococcal meningitis (CM), but its immunopathogenesis is poorly understood. We compared circulating T cell memory subsets and cytokine responses among 17 HIV-infected Ugandans with CM: 11 with and 6 without CM-IRIS. At meningitis diagnosis, stimulation with cryptococcal capsule component, glucuronoxylomannan (GXM) elicited consistently lower frequencies of CD4+ and CD8+ T cell memory subsets expressing intracellular cytokines (IL-2, IFN-γ and IL-17) among subjects who subsequently developed CM-IRIS. After ART initiation, T cells evolved to show a decreased CD8+ central memory phenotype. At the onset of CM-IRIS, stimulation more frequently generated polyfunctional IL-2+/IL-17+ CD4+ T cells in patients with CM-IRIS. Moreover, CD8+ central and effector memory T cells from CM-IRIS subjects also demonstrated more robust IL-2 responses to antigenic stimulation vs. controls. Thus, ART during CM elicits distinct differences in T cell cytokine production in response to cryptococcal antigens both prior to and during the development of IRIS, suggesting an immunologic foundation for the development of this morbid complication of CM infection.
REVIEW | doi:10.20944/preprints202012.0795.v1
Subject: Life Sciences, Biochemistry Keywords: T cells; chimeric antigen receptor; transgenic T-cell receptor; tumor-infiltrating lymphocytes; exhaustion; terminal differentiation; senescence; apoptosis; adoptive cell transfer; immunotherapy
Online: 31 December 2020 (12:16:55 CET)
Over the last decades, cellular immunotherapy has revealed its curative potential. However, the inherent physiological characteristics of immune cells can limit the potency of this approach. Best defined in T cells, dysfunction associated with terminal differentiation, exhaustion, senescence, and activation-induced cell death undermine adoptive cell therapies. In this review, we concentrate on how the multiple mechanisms that articulate the various forms of immune dysfunction impact cellular therapies primarily involving conventional T cells, but also other lymphoid subtypes, in addition to the various strategies put in place to circumvent these effects. The repercussions of immune cell dysfunction across the full life cycle of cell therapy, from the source material, during manufacturing, and after adoptive transfer are discussed. Applicable to cellular products prepared from native and unmodified immune cells, as well as genetically engineered therapeutics, the understanding and potential modulation of dysfunctional features is key to the development of improved cellular immunotherapies.
REVIEW | doi:10.20944/preprints202101.0388.v1
Subject: Life Sciences, Biochemistry Keywords: Thymic selection; T-cell development; T-cell receptor (TCR); mathematical modelling; multiscale models; complex systems; ordinary differential equations (ODE); agent-based models.
Online: 19 January 2021 (16:39:50 CET)
The thymus hosts the development of a specific type of adaptive immune cells called T cells. T cells orchestrate the adaptive immune response through recognition of antigen by the highly variable T-cell receptor (TCR). T-cell development is a tightly coordinated process comprising lineage commitment, somatic recombination of Tcr gene loci and selection for functional, but non-self-reactive TCRs, all interspersed with massive proliferation and cell death. Thus, the thymus produces a pool of T cells throughout life capable of responding to virtually any exogenous attack while preserving the body through self-tolerance. The thymus has been of considerable interest to both immunologists and theoretical biologists due to its multiscale quantitative properties, bridging molecular binding, population dynamics and polyclonal repertoire specificity. Here, we review mathematical modelling strategies that were reported to help understand the flexible dynamics of the highly dividing and dying thymic cell populations. Furthermore, we summarize the current challenges to estimating in vivo cellular dynamics and to reaching a next-generation multiscale picture of T-cell development.
ARTICLE | doi:10.20944/preprints202102.0315.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Brain Metastasis; Immune Checkpoint; Tumor Microenvironment, T-cells, TILs
Online: 15 February 2021 (15:06:48 CET)
The heterogeneity of tumor infiltrating lymphocytes is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune cell subsets in brain metastasis tissues to test which immunosuppressive routes are involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on twenty formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and Iba1, and analyzed an average of 15000 cells per sample. We classified tumours as either high (>30%) or low (<30%) tumour infiltrating lymphocytes (TILs) and found that increased TILs density correlated with survival. We next sought out to phenotype these TILs using mIF. The tumours with low TILs (n=9) had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p<0.01) as well as in their microenvironment (p<0.001). Contrastingly, the brain metastatic tumours with high TILs (n=8) displayed higher levels of activated microglia, as measured by Iba1 expression. Low TILs-tumours displayed CD8+ T-cells that co-express VISTA (p<0.01) significantly more compared to high TILs group, where CD8+ T-cells significantly co-express Iba1 (p<0.05). Interestingly, no definite phenotypes of CD4+ subsets were observed. These results were supported by RNA analysis of a publicly available, independent cohort. In conclusion, our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.
ARTICLE | doi:10.20944/preprints202106.0030.v1
Online: 1 June 2021 (11:59:27 CEST)
Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Currently, there are no reports on the mycobacterial components that regulate PGE2 production. Previously, we have reported that RpfE-treated dendritic cells (DCs) effectively expanded the Th1 and Th17 cell responses simultaneously; however, the mechanism underlying Th1 and Th17 cell differentiation is unclear. Here, we show that PGE2 produced by RpfE-activated DCs via the MAPK and cyclooxygenase 2 signaling pathways induces Th1 and Th17 cell responses mainly via the EP4 receptor. Furthermore, mice administered intranasally with PGE2 displayed RpfE-induced antigen-specific Th1 and Th17 responses with a significant reduction in bacterial load in the lungs. Furthermore, the addition of optimal PGE2 amount to IL-2-IL-6-IL-23p19-IL-1β was essential for promoting differentiation into Th1/Th17 cells with strong bactericidal activity. These results suggest that RpfE-matured DCs produce PGE2 that induces Th1 and Th17 cell differentiation with potent anti-mycobacterial activity.
Subject: Life Sciences, Biochemistry Keywords: Swine IAV; Immunoinformatics; T cell epitope conservation
Online: 17 March 2021 (10:55:56 CET)
When swine flu vaccines and circulating influenza A virus (IAV) strains are poorly matched, vaccine-induced antibodies may not protect from infection. Highly conserved T cell epitopes may, however, have a disease-mitigating effect. The degree of T cell epitope conservation among circulating strains and vaccine strains can vary, which may also explain differences in vaccine efficacy. Here, we evaluate a previously developed conserved T cell epitope-based vaccine and determine the persistence of T cell epitope conservation over time. We used a pair-wise homology score to define conservation between the vaccine’s swine leukocyte antigen (SLA) class I and II-restricted epitopes and T cell epitopes found in 1,272 swine IAV strains sequenced between 2013 and 2017. Twenty-four of the 48 total T cell epitopes included in the epitope-based vaccine were highly conserved and found in >1,000 circulating swine IAV strains over the five-year period. In contrast, commercial swine IAV vaccines developed in 2013 exhibited declining conservation with the circulating IAV strains over the same five-year period. Conserved T cell epitope vaccines may be useful adjunct for commercial swine flu vaccines and to improve protection against influenza when antibodies are not cross-reactive.
ARTICLE | doi:10.20944/preprints202108.0492.v1
Subject: Life Sciences, Immunology Keywords: Leishmania; Vaccine; T-cell Epitopes; Hamster; IFN-γ epitope; Sterile Immunity
Online: 25 August 2021 (12:34:26 CEST)
Visceral Leishmaniasis is a neglected tropical disease affecting 12 million people annually. Even in the second decade of the 21st century, it has remained without an effective vaccine for human use. In the current study, we have designed three multiepitope vaccine candidates by the selection of multiple IFN-γ inducing MHC-I and MHC-II binder T-cell specific epitopes from 3 previously identified antigen genes of Leishmania donovani from our lab, by immune-informatic approach using IFNepiotpe, NET-MHC-1 and NET MHC-2 webservers. We have tested the protective potential of these three multiepitope proteins as vaccine in a hamster model of visceral leishmaniasis. The immunization data revealed that the vaccine candidates induced a very high level of Th-1 biased protective immune response in-vivo in a hamster model of experimental visceral Leishmaniasis, with one of the candidates inducing a sterile immunity. The vaccinated animals displayed highly activated monocyte macrophages with the capability of clearing intracellular parasites due to increased respiratory burst. Additionally, these proteins induced activation of polyfunctional T cells secreting INF-γ, TNF-α, and IL-2 in ex-vivo stimulation of human peripheral blood mononuclear cells, further supporting the protective nature of designed candidates.
REVIEW | doi:10.20944/preprints202110.0368.v1
Online: 25 October 2021 (15:48:05 CEST)
Findings of new targeted treatments with adequate safety evaluations is essential for better cancer cures and mortality rates. Immunotherapy holds promise for patients with relapsed disease, with the ability to elicit long-term remissions. Emerging promising clinical results in B-cell malignancy using gene-altered T-lymphocytes uttering chimeric antigen receptors have sparked a lot of interest. This treatment could open the path for a major difference in the way we treat tumors that are resistant or recurring. Genetically altered T cells used to produce tumor-specific chimeric antigen receptors are resurrected field of adoptive cell therapy by demonstrating remarkable success in the treatment of malignant tumors. Because of the molecular complexity of chimeric antigen receptors -T cells, a variety of engineering approaches to improve safety and effectiveness are necessary to realize larger therapeutic uses. In this study, we investigate at new strategies for enhancing chimeric antigen receptors-T cell therapy by altering chimeric antigen receptors proteins, T lymphocytes, and their relations with other solid tumor microenvironment (TME) aspects.
ARTICLE | doi:10.20944/preprints202001.0146.v1
Subject: Engineering, Automotive Engineering Keywords: child seats; car accidents; car crash analyses; children safety
Online: 15 January 2020 (07:30:38 CET)
The study presents a comparison of the common Child Restraint Systems (CRS) which reduces the value of dynamic loads affecting the child's body during car accidents. The analyzed systems were: child seats, Combi Booster Seats, and straps adjusting vehicle seat belts to children's sizes. The effectiveness of the analyzed devices was assessed on the basis of experimental tests carried out in the accredited laboratory approving the Child Restraint Systems. The tests were carried out accordingly to the new Regulation No. 129 UN / ECE. Whether the tested devices meet the guidelines of the new Regulations No. 129 despite approval in accordance with Regulation No. 44. Based on the research result, better safety parameters of some new solutions dedicated to children’s safety could be observed. The final results show that there is still space for improving the safety of young vehicle passengers.
ARTICLE | doi:10.20944/preprints201912.0098.v1
Subject: Engineering, Automotive Engineering Keywords: child seats; car accidents; car crash analyses; children safety
Online: 8 December 2019 (15:45:04 CET)
The study presents a comparison of the common Child Restraint Systems (CRS) which reduces the value of dynamic loads affecting the child's body during car accidents. The analyzed systems were: child seats, Combi Booster Seats, and straps adjusting vehicle seat belts to children's sizes. The effectiveness of the analyzed devices was assessed on the basis of experimental tests carried out in the accredited laboratory approving the Child Restraint Systems. The tests were carried out accordingly to the new Regulation No. 129 UN / ECE. Whether the tested devices meet the guidelines of the new Regulations No. 129 despite approval in accordance with Regulation No. 44. Based on the research result, better safety parameters of some new solutions dedicated to children's safety could be observed. The final results show that there is still space for improving the safety of young vehicle passengers.
ARTICLE | doi:10.20944/preprints202004.0509.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: nodal peripheral T-cell lymphomas; peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS); ALK-negative anaplastic large-cell lymphoma (ALCL/ALK-); Angioimmunoblastic T-cell lymphoma (AITL); diagnosis; prognosis; GATA3 gene expression
Online: 29 April 2020 (12:48:00 CEST)
Background: Nodal peripheral T-cell lymphomas (nPTCLs) encompass a heterogeneous group of mature and aggressive lymphoid malignancies, including peripheral T-cell lymphoma, not otherwise specified (PTCL/NOS), angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL) ALK-positive and ALK-negative. Their differential diagnosis and prognosis are an issue in the clinical practice. Accurate biomarkers to refine the different subtypes of nPTCLs and to stratify their prognosis are essential to improve their treatment approach. The aim of this study was to test the prognostic impact of GATA3 gene expression, and its capability to discriminate the different subtypes of nPTCLs. Patients and Methods: From 2000 to 2017, 80 patients with nPTCLs were eligible for GATA3 gene expression analysis that was assessed retrospectively by quantitative real time PCR (qRT-PCR) of neoplastic biopsies in Formalin-Fixed Paraffin-Embedded samples (FFPE). Results: Median age was 49 years old (IqR 34-59), 43/80 (53.7%) were male. Median follow-up was 1.72 years. Of them, 36.3% were classified as PTCL/NOS, 31.2% ALK-negative ALCL, 21.2% ALK-positive ALCL and 11.3% AITL. The majority of cases had advanced stage (III/IV). Two-year estimated overall survival (OS) and progression-free survival (PFS) were 52.2% and 39.5%, respectively. The median GATA3 gene expression level was 0.49% (range 0 – 7.07) in all cohort, it was 0.11% for ALK-positive ALCL, 0.46% for ALK-negative ALCL, 0.86% for PTCL/NOS and 0.67% for AITL. The difference of GATA3 gene expression among distinct variants of nPTCLs was statistically significant (p < 0.001). GATA3 gene expression levels ≥ 0.71% discriminate PTCL/NOS from ALK-negative ALCL and AITL with sensitivity of 62% and specificity of 80.3%. GATA3 gene expression levels ≥ median was associated with poor 2-year OS for PTCL/NOS (46.7% x 21.4%, p=0.04) and for ALK-negative ALCL (85.7% x 54.5%, p=0.04). Conclusion: Despite the relative small and heterogeneous group of patients with nPTCLs, GATA3 gene overexpression may be an important biomarker associated with poor prognosis in PTCL/NOS and ALK-negative ALCL. Moreover it may also discriminate different subtypes of nPTCLs. Further studies with larger series of patients should confirm our findings.
REVIEW | doi:10.20944/preprints202012.0419.v1
Subject: Medicine & Pharmacology, Allergology Keywords: immune checkpoint; lymphoid neoplasms; programmed death 1; cytotoxic T-lymphocyte antigen 4; monoclonal antibodies; combination therapies
Online: 17 December 2020 (08:10:05 CET)
Immunotherapy has been considered for years as a viable and attractive treatment option for patients with cancer. Among immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionized the treatment of several subtypes of tumours. These approaches aimed at restoring an effective anti-tumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells, and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because in these diseases the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and will build a projection of how the field may evolve in the near future. In particular, we will analyze the current strategies being evaluated both preclinically and clinically with the aim to foster the use of immune-checkpoint inhibitors in non-Hodgkin lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.
REVIEW | doi:10.20944/preprints202007.0016.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: myeloma; BCMA; bispecific T-cell engager; antibody-drug conjugates; chimeric antigen receptor T-cells; belantamab mafodotin; idecabtagene vicleucel; JNJ-68284528
Online: 3 July 2020 (07:30:57 CEST)
During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.
ARTICLE | doi:10.20944/preprints202106.0149.v1
Subject: Life Sciences, Biochemistry Keywords: vaccine; Staphylococcus aureus; T cell response; mastitis; bovine
Online: 7 June 2021 (07:54:02 CEST)
Staphylococcus aureus mastitis remains a major challenge for dairy farming. Here, 24 mice were immunized and divided into four groups: G1: control; G2: Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF) DNA vaccine; G3: F0F1 ATP synthase subunit α (SAS), succinyl-diaminopimelate (SDD), and cysteinyl-tRNA synthetase (CTS) recombinant proteins; and G4: SAS+SDD+CTS plus GM-CSF DNA vaccine. The lymphocyte subpopulations and the intracellular interleukin-17A (IL-17A) and interferon-γ production in the draining lymph node cells were immunophenotyped by flow cytometry. The immunophenotyping and lymphocyte proliferation was determined in spleen cells cultured with and without S. aureus stimulus. Immunization with S. aureus recombinant proteins generated memory cells in draining lymph nodes. Immunization with the three recombinant proteins plus GM-CSF DNA led to an increase in the percentage of IL-17A+ cells among overall CD44+ (memory), T CD4+, CD4+ T CD44+ CD27-, γδ TCR, γδ TCR+ CD44+ CD27+ and TCRVγ4+ cells. Vaccination with S. aureus recombinant proteins associated with GM-CSF DNA vaccine downregulates TH2 immunity. Immunization with the three recombinant proteins plus the GM-CSF DNA led to a proliferation of overall memory T, CD4+ and CD4+ TEM cells upon S. aureus stimulus. This approach fostered type 3 immunity, suggesting the development of a protective immune response against S. aureus.
ARTICLE | doi:10.20944/preprints202105.0142.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Cancer Immunotherapy; Cancer Vaccine; Cancer Antigens; CRISPR-Cas9; Engineered T Cells.
Online: 7 May 2021 (11:10:13 CEST)
The mechanisms involved in immune responses to cancer have been extensively studied for several decades and, considerable attention has been paid to harnessing the immune system's therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell-cancer therapy and immune test therapy have gained prominence through immunotherapy. However, it remains to be accomplished the full potential of cancer immunotherapy. In spite of having startling aspects, the cancer immunotherapies have some difficulties including the inability to effectively targeting the cancer antigens and the abnormalities in patient response. With the advancement of technology, this system has changed the genome-based immunotherapy process in the human body including generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome-editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR-T cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR-T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against the cancer. In this review, we have broadly focused on the use of CRISPR-Cas9 technology for the modification of the T-cell, which can specifically recognize cancer cells and be used as immune therapeutics against cancer. We have also demonstrated the other potential strategies for the treatment of cancer.
REVIEW | doi:10.20944/preprints201912.0393.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: cutaneous lymphoma in elderly; skin tumors; T-cell lymphomas; sport activity training
Online: 30 December 2019 (05:43:39 CET)
PcALCL mainly concerns elderly patients. It is a large CD30+ T-cell neoplasm composed of large cells with anaplastic, pleomorphic or immunoblastic morphology, with exclusively cutaneous onset and localization. The clinical course of pcALCL is predominantly indolent. Most elderly patients with lymphoma tend to have a sedentary lifestyle, which has a negative effect on their quality of life (QoL) and on their survival. Several studies indicate that exercise has a positive impact on QoL because it reduces peak oxygen consumption, improves physical capacity, increases self-esteem, reduces accumulated stress and promotes relaxation. Therefore, particularly in indolent lymphomas, it is necessary to indicate a program of physical activity to be practiced systematically. The complete surgical excision and local radiotherapy are the first line gold standard in pcALCL with solitary lesion.
REVIEW | doi:10.20944/preprints202201.0073.v1
Subject: Medicine & Pharmacology, Other Keywords: Messenger RNA • Hospital-based mRNA therapeutics • circular mRNA • self-amplifying mRNA • RNA-based CAR T-cell • RNA-based gene-editing tools
Online: 6 January 2022 (11:20:59 CET)
Hospital-based programs democratize mRNA therapeutics by facilitating the processes to translate a novel RNA idea from the bench to the clinic. Because mRNA is essentially biological software, therapeutic RNA constructs can be rapidly developed. The generation of small batches of clinical grade mRNA to support IND applications and first-in-man clinical trials, as well as personalized mRNA therapeutics delivered at the point-of-care, is feasible at a modest scale of cGMP manufacturing. Advances in mRNA manufacturing science and innovations in mRNA biology, are increasing the scope of mRNA clinical applications.
REVIEW | doi:10.20944/preprints202103.0262.v1
Subject: Medicine & Pharmacology, Other Keywords: immune checkpoint inhibitors; immune checkpoint radiolabeled antibodies; PD-1; PD-L1; immune PET; immunotherapy; AI; Radiomics; Deep learning; CAR-T cells
Online: 9 March 2021 (11:12:55 CET)
Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using immunohistochemical analysis of the expression of anti-gens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells, and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET, in general, is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers) able to identify specific immune system targets are under investigation in pre-clinical and clinical settings. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells, and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [18F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).
ARTICLE | doi:10.20944/preprints201901.0065.v1
Subject: Life Sciences, Immunology Keywords: acute HIV infection; vaccines; CD8$^+$ T cells; immune response; multiple epitopes; competition; mathematical model
Online: 8 January 2019 (11:22:41 CET)
Multiple lines of evidence indicate that CD8$^+$ T cells are important in the control of HIV-1 (HIV) replication. However, CD8$^+$ T cells induced by natural infection cannot eliminate the virus or reduce viral loads to acceptably low levels in most infected individuals. Understanding the basic quantitative features of CD8$^+$ T-cell responses induced during the course of HIV infection may therefore inform us about the limits that HIV vaccines, which aim to induce protective CD8$^+$ T-cell responses, must exceed. Using previously published experimental data from a cohort of HIV-infected individuals with sampling times from acute to chronic infection we defined the quantitative properties of CD8$^+$ T-cell responses to the whole HIV proteome. In contrast with a commonly held view, we found that the relative number of HIV-specific CD8$^+$ T-cell responses (response breadth) changed little over the course of infection (first 400 days post-infection), with moderate but statistically significant changes occurring only during the first 35 symptomatic days. This challenges the idea that a change in the T-cell response breadth over time is responsible for the slow speed of viral escape from CD8$^+$ T cells in the chronic infection. The breadth of HIV-specific CD8$^+$ T-cell responses was not correlated with the average viral load for our small cohort of patients. Metrics of relative immunodominance of HIV-specific CD8$^+$ T-cell responses such as Shannon entropy or the Evenness index were also not significantly correlated with the average viral load. Our mathematical-model-driven analysis suggested extremely slow expansion kinetics for the majority of HIV-specific CD8$^+$ T-cell responses and the presence of intra- and interclonal competition between multiple CD8$^+$ T-cell responses; such competition may limit the magnitude of CD8$^+$ T-cell responses, specific to different epitopes, and the overall number of T-cell responses induced by vaccination. Further understanding of mechanisms underlying interactions between the virus and virus-specific CD8$^+$ T-cell response will be instrumental in determining which T-cell-based vaccines will induce T-cell responses providing durable protection against HIV infection.
ARTICLE | doi:10.20944/preprints202105.0151.v1
Online: 7 May 2021 (16:19:15 CEST)
Despite the use of commercial forest carbon protocols (CFCPs) for more than two decades, claiming ~566 MMtCO2e and a market value of ~USD $15.7 billion, comparative analysis of CFCP methodology and offset results is limited. In this study, five widely used biometric-based CFCPs were characterized, and common characteristics and differences were identified. CFCP claims of net forest carbon sequestration are compared with results of directly measured CO2 by eddy covariance, a meteorological method integrating gross vertical fluxes of forest and soil carbon, and the only alternative non-biometric source of net forest carbon sequestration data available. We show here that CFCPs share a structural feature delimiting forest carbon values by zero-threshold carbon accounting (gC m-2 ≤ 0), a pattern opposite to natural emissions of forest CO2 exchange based on direct measurement and a fundamental biological constraint on net forest carbon storage (i.e., soil efflux, ecosystem respiration). Exclusion of forest CO2 sources to the atmosphere precludes net carbon accounting, resulting in unavoidable over-crediting of CFCP offsets. CFCP carbon results are significantly different from global forest CO2 net ecosystem exchange population results (FluxNet2015 gC m-2) at the 95% to 99.99% confidence levels, inferring an annual median error of ~247% (gC m-2), also consistent with over-crediting. Direct CO2 measurement provides an alternative method for commercial forest carbon products, has the potential to harmonize global markets, and catalyze the role of forests in managing climate change through nature-based solutions.
ARTICLE | doi:10.20944/preprints201807.0407.v1
Subject: Life Sciences, Microbiology Keywords: neisseria gonorrhoeae; gonorrhea; vaccine; microneedle; skin patch; nanotechnology; antigen-specific antibody; antigen-specific CD4 T lymphocytes
Online: 23 July 2018 (09:43:29 CEST)
Neisseria gonorrhoeae is a strict human pathogen responsible for more than 100 million new sexually transmitted infections worldwide each year. Due to the global emergence of antibiotic resistance, the CDC recently listed N. gonorrhoeae as an urgent threat to public health. No vaccine is available in spite of the huge disease burden and the possibility of untreatable gonorrhea. The aim of this study is to investigate the immunogenicity of a novel whole-cell based inactivated gonococcal microparticle vaccine formulation loaded in dissolvable microneedles for transdermal administration. The nanotechnology-based vaccine formulation consists of inactivated whole-cell gonococci strain CDC-F62, spray dried and encapsulated into biodegradable cross-linked albumin matrix with sustained slow antigen release. The dry vaccine nanoparticles were then loaded in a dissolvable microneedle skin patch for transdermal delivery. The efficacy of the whole-cell microparticles vaccine formulation loaded in microneedles was assessed in vitro using dendritic ,cells and macrophages as well as in vivo mouse model. Antibody titers were measured using an ELISA and antigen-specific T lymphocytes were assessed in spleens and lymph nodes. Here we report that whole-cell based gonococcal microparticle vaccine loaded in dissolvable microneedles for transdermal administration induced significant increase in antigen-specific IgG antibody titers and antigen-specific CD4 and CD8 T lymphocytes in mice compared to gonococcal antigens in solution or empty microneedles. Significant increase in antigen-specific IgG antibody levels was observed at end of week 2 in groups that received the vaccine compared to the group receiving empty nanoparticles. The advantages of using formalin-fixed whole-cell gonococci that all immunogenic epitopes are covered and preserved from degradation. The spherical shaped micro and nanoparticles are biological mimics of gonococci, therefore present to the immune system as invaders but without the ability to suppress adaptive immunity. In conclusion, the transdermal delivery of microparticles vaccine via a microneedle patch was shown to be an effective system for vaccine delivery. The novel gonorrhea nanovaccine is cheap to produce in a stable dry powder and can be delivered in microneedle skin patch obviating the need for needle use or the cold chain.
REVIEW | doi:10.20944/preprints202012.0794.v1
Subject: Social Sciences, Accounting Keywords: sustainability; urban sustainability; car-sharing; Europe
Online: 31 December 2020 (12:16:02 CET)
(1) Background: The article gives us an insight into the key issues of the car-sharing and its impact on urban sustainability. (2) Methods: A selection of 314 articles published in peer-reviewed journals from the Scopus database were analysed using Leximancer 5.0 for Automated Content analysis. (3) Results: Seven themes were identified explaining the researched topic of the car-sharing situation in Europe, which are Sharing, Economy, Model, Systems, Electrical car-sharing, Policy and Travel. There are two ways of sharing owned cars in Europe, access to cars from the fleet of private organizations and P2P car-sharing. Sustainable environmental solutions in the context of the electrification of cars are used. Car-sharing usually takes place online and can be free or for a free as defined by The European Economic and Social Committee. (4) Conclusions: The article provides an overview of understanding the concept of urban car-sharing in Europe.
ARTICLE | doi:10.20944/preprints202012.0160.v1
Subject: Keywords: melanoma; genetic whole cell therapeutic melanoma vaccine (AGI-101H); CD8+ T cells; melanoma antigens; ELISPOT
Online: 7 December 2020 (13:53:31 CET)
Healthy human subjects develop spontaneous CD8+ T cell responses to melanocyte antigens (MA) expressed by normal melanocytes, such as Tyrosinase, MAGE-A3, Melan/Mart-1, gp100, and NY-ESO-1. This natural autoimmunity directed against melanocytes might confer protection against the development of malignant melanoma (MM), where MA are present as overexpressed tumor-associated antigens. Consistent with this notion we report here that functional T cell reactivity to MA was found to be diminished in untreated MM patients: while 57.5% of healthy controls (n=40) exhibited high-frequency MA-specific T cell reactivity ex vivo, such was detected in only 12% of the untreated MM patients (n=24). Three lines of evidence suggest that the MA-reactive T cells present in healthy subjects undergo exhaustion once MM establishes itself. First, only the MA-specific T cell reactivity was affected in the MM patients; that to third party recall antigens was not. Second, in these patients, the residual MA-specific T cells, unlike third party antigen reactive T cells, were functionally impaired, showing a diminished per cell IFN-γ productivity. Third, successful immunotherapy with AGI-101H melanoma vaccine restored natural CD8+ T cell autoimmunity to MA in 85% of the vaccinated patients (n= 27). The role of natural T cell autoimmunity to tumor-associated MA is discussed based on discrete levels of T cell activation thresholds.
ARTICLE | doi:10.20944/preprints202008.0092.v1
Subject: Keywords: COVID-19; SARS-CoV-2; epitopes; B-cell; T-cell; immuno informatics; MHC-I; MHC-II
Online: 4 August 2020 (11:18:27 CEST)
Coronavirus disease (COVID-19) is a new discovered strain where WHO officially declares the disease as COVID-19 while the virus responsible for it called Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2. The incubation period of this disease is between 14 days. Ordinary clinical symptoms that reported around the world include fever, cough, fatigue, diarrhoea and vomiting as well as asymptomatic for certain people. Infection is spread mainly through broad droplets. In early March 2020, WHO again has announced that COVID-19 is a pandemic with currently no specific treatment. The potential use of SARS-COV-2 proteome as a vaccine candidate by analysing through B-cell and T-cell antigenicity by using a immunoinformatics approach as a vaccine development early stage. In this study, we used consensus sequence for SARS-COV-2 proteome that was retrieved from NCBI database. VaxiJen 2.0 was mainly used to identify the antigenic property of SARS-COV-2 proteins. IEDB then used to analyse the B-cell epitope, the presence of T cell immunogenic epitope in SARS-COV-2 proteins was obtained by using compromise method of MHC class I and II tools that accessible respectively using ProPred-1 server and MHC II Binding Prediction in IEDB database. The best epitopes of B and T-cell epitopes were predicted with high antigencity and the information is disseminated through web-based database resource (https://covid-19.omicstutorials.com/epitopes/). This study will be useful to find a new epitope-based candidate for SARS-COV-2. However, further study needs to be done for the next stages of vaccine development.
HYPOTHESIS | doi:10.20944/preprints202108.0270.v1
Subject: Biology, Other Keywords: T helper differentiation; T helper polarization; Cross-reactivity; Regulatory T cells; Microbiota; Original Antigenic Sin
Online: 12 August 2021 (08:46:55 CEST)
Naive CD4+ T cells engage cognate peptide MHC-II complexes (pMHC-IIs) to differentiate and acquire one of several T helper (Th) fates whose specific trajectories are guided by a dynamic cytokine milieu that develops in response to antigenic entity. This physiological process is often erroneously conflated with a pathological one termed Th polarization. Using the SPIRAL model, we argue here that unlike Th fate choice, innate signaling alone is insufficient to initiate Th polarization in naive CD4+ T cells, that it instead develops from pre-existing memory CD4+ T cells that express cross-reactive TCRs, and that it inevitably leads to immunopathology.
ARTICLE | doi:10.20944/preprints201903.0042.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: pancreatic cancer, T cells, cancer stem cells, CD8, PD-L1, CD44, CD133, immunotherapy
Online: 4 March 2019 (13:28:43 CET)
Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effect to evade the immune recognition. However, clinical implications of the associations among CD8+ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8+ T cells infiltration, PD-L1 expression, and their relationship with CD44+/CD133+ CSCs and disease progression in PC. CD8+ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8+ T cells infiltration/high PD-L1 expression group and the high CD8+ T cells infiltration/high PD-L1 expression group show high levels of CD44+/CD133+ CSCs, but patients with low CD8+ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8+ T cells infiltration/high PD-L1 expression. Moreover, CD8+ T cells infiltration could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8+ T cells infiltration, PD-L1 expression, and CD44+/CD133+ CSCs existence, which contributes to PC progression and immune evasion.
ARTICLE | doi:10.20944/preprints201911.0149.v1
Subject: Engineering, Other Keywords: car sharing; forecasting; machine learning; socio-demographic; weather
Online: 13 November 2019 (12:31:49 CET)
Free Floating Car Sharing (FFCS) services are a flexible alternative to car ownership. These transportation services show highly dynamic usage both over different hours of the day, and across different city areas. In this work, we study the problem of predicting FFCS demand patterns -- a problem of great importance to an adequate provisioning of the service. We tackle both the prediction of the demand i) over time and ii) over space. We rely on months of real FFCS rides in Vancouver, which constitute our ground truth. We enrich this data with detailed socio-demographic information obtained from large open-data repositories to predict usage patterns. Our aim is to offer a thorough comparison of several machine learning algorithms in terms of accuracy and easiness of training, and to assess the effectiveness of current state-of-art approaches to address the prediction problem. Our results show that it is possible to predict the future usage with relative errors down to 10%, and the spatial prediction can be estimated with relative errors of about 40%. Our study also uncovered the socio-demographic features that most strongly correlate with FFCS usage, providing interesting insights for providers opening service in new regions.
REVIEW | doi:10.20944/preprints201907.0211.v2
Subject: Medicine & Pharmacology, Pathology & Pathobiology Keywords: HIV-1; CRISPR-Cas9; T-cells; lipid nanoparticles; gut-associated-lymphoid tissue; Co-receptors; Probiotics; GI Tract,; Gene Editing
Online: 13 April 2020 (10:57:52 CEST)
HIV-1 is a complicated and perplexing virus. It infects T cells, reverse transcribes its RNA into DNA, utilizes its host DNA machinery to replicate its HIV-DNA, translates the HIV-DNA into proteins, assembles itself for a budding escape from the T cell, and rapidly mutates its conformation. Partially, due to its complexity, there remains no cure for HIV or AIDs. However, recently with the discovery of TALENs, the use of zinc fingers, and most of all the applications of CRISPR-Cas9 technology, has given researchers new hope in finding alternative gene therapies and treatments for diseases. With more focus on CRISPR-Cas9, this new and novel technology uses a guiding RNA, sgRNA, to lead a Cas9 nuclease to its target for deletion or to change that DNA site. CRISPR-Cas9 can delete point mutations and multiple DNA sites. Because CRISPR can alter DNA sequences, several scientists have conducted research into CRISPR, possibly treating more diseases such as cancer, diabetes, and even HIV. HIV-1 drew the focus of a researcher named Dr. Ebina in 2013 when he was the first to design and apply CRISPR-Cas9 to genes found in the binding sites of HIV-1, inhibiting HIV-1 gene expression. Since 2013, several other researchers have blocked HIV replication and infection through CRISPR-Cas9 targeting the receptors of T cells called the CC chemokine receptor 5 or CCR5. HIV-1 binds to the CD4 receptor of T cells, which consists of co-receptors CCR5 and CXCR4. If CCR5 expression can be removed, the HIV virus cannot bind to T-cells, blocking the initial attachment stage, and discontinuing the infection. However, there remain obstacles and issues for the CRISPR deletion of CCR5 for treating HIV-1. The issues include: 1) finding new and safe methods of CRISPR-Cas9 delivery, 2) clearing the latent HIV reservoirs, 3) improving the sgRNA design to avoid off-target mutations or deletions, and 4) effectively analyze the viral escape of HIV from CRISPR-Cas9 modifications. Therefore, the purpose of this review is to discuss possible techniques for removing the obstacles that can lessen the potential of CRISPR to delete CCR5, repressing HIV-1 into long-term remission or a functional cure.
ARTICLE | doi:10.20944/preprints202112.0377.v1
Subject: Life Sciences, Genetics Keywords: pig genome; gamma/delta T-cell; TRG locus; TRG genes; gamma/delta high species; Cetartiodac-tyla; Immunogenomics; evolution
Online: 23 December 2021 (10:02:37 CET)
The domestic pig (Sus scrofa) is a species representative of the Suina, one of the four suborders within Cetartiodactyla. In this paper, we reported our analysis of the pig TRG locus in comparison with the loci of species representative of the Ruminantia, Tylopoda and Cetacea suborders. The pig TRG genomic structure reiterates the peculiarity of the organization of Cetartiodactyla loci in TRGC “cassettes”, each containing the basic V-J-J-C unit. Eighteen genes arranged in four TRGC cassettes, form the pig TRG locus. All the functional TRG genes were expressed, and the TRGV genes preferentially rearrange with the TRGJ genes within their own cassette, which correlates the diversity of the gamma-chain repertoire with the number of cassettes. Among them, the TRGC5, located at the 5’ end of the locus, is the only cassette that retains a marked homology with the corresponding TRGC cassettes of all the analyzed species. The preservation of the TRGC5 cassette for such a long evolutionary time presumes a highly specialized function of its genes, which could be essential for the survival of species. Therefore, the maintenance of this cassette in pigs confirms that it is the most evolutionarily ancient within Cetartiodactyla, and it has undergone a process of duplication to give rise to the other TRGC cassettes in the different artiodactyl species in a lineage-specific manner.
ARTICLE | doi:10.20944/preprints201810.0163.v1
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: T-UCR; pediatric acute lymphoblastic leukemia; uc.112; T-ALL; hyperdiploidy.
Online: 8 October 2018 (17:01:03 CEST)
Long non-coding RNA (lncRNA) aberrant expression have been found in several types of cancer, including acute lymphoblastic leukemia (ALL), but lncRNA mapped in transcribed ultraconserved regions (T-UCRs) are little explored. The T-UCRs uc.112, uc.122, uc.160 and uc.262 were evaluated in pediatric ALL and uc.112 expression was higher in T-ALL compared to patients with B-ALL and in patients with hyperdiploid karyotype. These findings suggest a potential role of this uc.112 in pediatric ALL and emphasize the need for further investigation of T-UCR in pediatric ALL.
REVIEW | doi:10.20944/preprints201905.0386.v1
Subject: Life Sciences, Immunology Keywords: CRISPR, clonal selection, totipotent, multipotent, T cell receptors, B cell receptors, precommitted, lymphocyte, T cell vaccine, T cell vaccination
Online: 31 May 2019 (11:12:33 CEST)
Transfer factor is the name given to material derived from activated lymphocytes that is probably composed of a complex of a peptide and a short segment of RNA and which has the reported ability to transfer specific T cell immunity to uncommitted lymphocytes. Many independent groups around the world reported isolating transfer factors between 1955 and 1990 and demonstrating their ability to transfer passive immunity from one animal or individual to another, often within 24 hours of inoculation. Such activity is potentially revolutionary both in making T cell vaccines readily manufacturable and also because the existence of transfer factors would undermine the basic assumptions of the clonal selection theory, which currently dominates immunological theory. Unfortunately, lack of the microanalytical and synthetic techniques required to properly identify transfer factors, combined with safety factors associated with it derivation from blood sources susceptible to HIV and prion infections, put an end to transfer factor research after 1990. This paper reviews the evidence supporting transfer factor activity and suggests that this potentially revolutionary concept be resurrected and subjected to renewed scrutiny in light of CRISPR-Cas mechanisms and because of its potential to make possible T cell vaccination and provide a novel basis for understanding immunological function.
REVIEW | doi:10.20944/preprints202111.0163.v1
Subject: Engineering, Industrial & Manufacturing Engineering Keywords: virtual reality; automotive industry; marketing research; immersive car clinic
Online: 9 November 2021 (11:01:16 CET)
Virtual reality (VR) can play a key role in automotive marketing research, lowering costs and shortening the time it takes to bring a new product to market. However, there are still few VR applications that support automotive customers' experiences during the early stages of product development. Through a systematic review of literature and patents, this study aims to identify the challenges and opportunities for the application of virtual reality in car clinics, and to categorize them into attributes. We searched through the knowledge databases of PatentScout, ScienceDirect, Springer, and IEEEXplore. We found 72 patents with a high concentration in a few inventors. The United States of America presented the greatest number of records and the most common applications related to the apparatus for automatically reading respondents' reactions in a virtual environment. In terms of articles, we found 19 research papers that discussed sixteen categories identified as challenges and opportunities for automotive marketing research: 1) cost, 2) location to customers, 3) flexibility in interactions, 4) model transportation, 5) depth perception, 6) haptic perception, 7) motion, 8) movement perception/ physical collision, 9) color and texture, 10) sound feedback, 11) product interaction/manipulation, 12) visual-spatial, 13) graphic quality, 14) intuitiveness, 15) cybersecurity and 16) cybersickness. We conclude that the automotive industry can employ virtual reality for marketing research, but relevant elements such as hardware and software definition, stimulus quality, and research objectives, among others, must be considered.
ARTICLE | doi:10.20944/preprints201805.0296.v1
Subject: Mathematics & Computer Science, Other Keywords: normal intuitionistic fuzzy numbers; Heronian mean; Hamacher t-conorm; Hamacher t-norm
Online: 22 May 2018 (10:15:21 CEST)
Hamacher operation which is generalization of the Algebraic and Einstein operation, can widely provide a large number of arithmetical operation with respect to uncertainty information, and Heronian mean can deal with correlations of the input arguments or different criteria and don’t make calculation redundancy, meanwhile, the normal intuitionistic fuzzy numbers (NIFNs) can depict distinctively normal distribution information in practical decision making. In this paper, a multi-criteria group decision-making (MCGDM) problem is researched under the NIFNs environment, and a new MCGDM approach is introduced on the basis of the Hamacher operation. Firstly, according to Hamacher t-conorm and t-norm, some operational laws of NIFNs are presented. Secondly, it is noticed that Heronian mean can’t only once take into account mutual relation between attribute values once, but also consider the correlation between input argument and itself. Therefore, we develop some operators and study their properties in order to aggregate normal intuitionistic fuzzy numbers information, these operators include Hamacher Heronian mean (NIFHHM), Hamacher weighted Heronian mean (NIFHWHM), Hamacher geometric Heronian mean (NIFHGHM) and Hamacher weighted geometric Heronian mean (NIFHWGHM). Furthermore, we apply the proposed operators to the MCGDM problem and present a new method. The main characteristics of this new method involve that: (1) it is suitable to make decision under the normal intuitionistic fuzzy numbers environment and more reliable and reasonable to aggregate the normal distribution information. (2) it utilizes Hamacher operation which can provide more reliable and flexible decision-making results and offer an effective and powerful mathematic tool for the MAGDM under uncertainty. (3) it uses the Heronian mean operator which can considers relationships between the input arguments or the attributes and don’t brings subsequently about redundancy. Lastly, an application is given for showing the feasibility and effectiveness of the presented method in this paper.
ARTICLE | doi:10.20944/preprints202207.0206.v1
Subject: Life Sciences, Immunology Keywords: prime-boost immunization; tumor immunity; T cell memory; cytotoxic T cells; therapeutic vaccine
Online: 14 July 2022 (04:24:41 CEST)
Therapeutic vaccine studies should be designed to elicit durable, high magnitude, and efficacious T cell responses, all of which can be impacted by the choice of vaccination schedule. Here, we compare different prime-boost intervals (PBI) in a human papillomavirus (HPV) model using HPV16E6E7 Venezuelan equine encephalitis virus replicon particle (VRP) vaccination to address the optimal boosting schedule, quality of immune response, and overall in vivo efficacy. Six different vaccine regimens were tested with each group receiving booster vaccinations at different time intervals. Analysis of T-cell responses demonstrated a significant HPV16 E7 specific CD8+T cell response with minimally a one-week PBI between antigen re-exposure. Significant E7-specific in vivo cytotoxicity was also observed with longer PBIs. Additionally, longer PBIs led to an enhanced memory recall response to tumor challenge, which correlated with differential expansion of T cell memory subsets. Our findings imply that when using alphavirus vector platforms as a vaccination strategy, a one-week PBI is sufficient to induce high magnitude effector T cells with potent anti-tumor activity. However, longer PBIs lead to enhanced long-term protective anti-tumor immunity. These findings have implications for therapeutic vaccine clinical trials in which shorter intervals of prime-boost regimens may lead to suboptimal durable immune responses.
Subject: Engineering, Automotive Engineering Keywords: service quality; Kano; TRIZ; catering industrial; mobile catering car; TOPSIS
Online: 2 November 2020 (09:57:33 CET)
This purpose of the study presented in this article is to comparing different service quality measurements between Kano and TRIZ that plays the critical roles in the catering industrial. Data collected from a DINESERV questionnaire comprises service-quality standards to increase customer satisfaction of mobile dining car. Finally, the TRIZ is standardized measure designed to improve the idealization of strategy for selecting the most appropriate service quality model. In addition, the preferences of more than one decision maker are internally aggregated into the TOPSIS procedure. All these things provide several important theoretical and practical implications for developing a successful mobile catering app.
ARTICLE | doi:10.20944/preprints201904.0165.v1
Subject: Engineering, Control & Systems Engineering Keywords: railway transportation; time-space network; dynamic bottleneck; car flow organization
Online: 15 April 2019 (11:44:10 CEST)
In this paper, the physical station of space network was extended in time dimension by combining the train diagram information and station technical operation standard time. At the same time, the topology of railway space-time network which considered the secondary operation process of train was constructed and an improved A* algorithm based on car flow routing was proposed to generate feasible path sets. On this basis, a dynamic car flow organization optimization model was built to simulate the railway car flow organization process under abnormal conditions, and the results of solving the model could be used to obtain the real-time quantity of cars at each station.This paper can identify the dynamic bottleneck by comparing the real-time quantity of cars with the maximum quantity of cars at the station. Finally, the feasibility of this method was analyzed and verified by a case.
ARTICLE | doi:10.20944/preprints201804.0119.v2
Online: 22 August 2020 (04:01:45 CEST)
The aim of this 9th expository article is to conclude a study on domination in two fuzzy models, including t−norm fuzzy graphs and fuzzy graphs. All parts are twofold even if we don’t men- tion, directly. I.e., all results depicts some properties about fuzzy graph and t−norm fuzzy graph.
ARTICLE | doi:10.20944/preprints202001.0018.v2
Subject: Engineering, Energy & Fuel Technology Keywords: photovoltaic; EV; PHV; standardization; car-roof; flexible PV; performance modeling; rating
Online: 15 January 2020 (07:19:23 CET)
The energy yield of the Vehicle-integrated photovoltaic (VIPV) differs from that of the standard photovoltaics (PV). It is mainly by the difference of the solar irradiance onto the car-roof and car-bodies as well as its curved-shape. Both meaningful and practical modeling and measurement of the solar irradiance for VIPV are needed to be newly established, not the extension of the current technologies. The solar irradiance was modeled by a random distribution of the shading objects and car-orientation with the correction of the curved surface of the PV modules. The measurement of the solar irradiance onto the car-roof and car-body was done using five pyranometers in five local axes on the car for one year. The measured dynamic solar irradiance onto the car-body and car-roof was used for validation of the solar irradiance model in the car.
REVIEW | doi:10.20944/preprints201805.0218.v1
Subject: Engineering, Energy & Fuel Technology Keywords: photovoltaic; standardization; EV; PHV; car-roof; flexible PV; performance modeling; rating
Online: 15 May 2018 (13:20:26 CEST)
A car-roof photovoltaic has an enormous potential to change our society. With this technology, 70% of the personal car can run by the solar energy collected by the solar panel on its car-roof. Unfortunately, it is not a simple extension of the conventional photovoltaic technology. This paper list what we need to do for realizing the future that majority of the personal cars run by renewable solar energy, after clarification of the difference from the conventional photovoltaic technology. In addition to the technological development, the standardization of this innovative technology will be important, and the list was made highlighting the standardization.
ARTICLE | doi:10.20944/preprints202111.0222.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: Takayasu arteritis; echocardiography; immune cell infiltration; vascular stiffness; T helper like cells; regulatory T lymphocytes
Online: 12 November 2021 (13:40:14 CET)
Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Hypertension and atherosclerosis lead to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression. Methods: Patients with active TAK arteritis were compared with age- and sex-matched hypertensive and atherosclerotic patients. In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical evaluation of the vessel wall was performed to compare the in vivo results. Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. These data have been associated with uric acid levels. A significant increase in aortic stiffness was also noted and associated with peripheral T lymphocyte levels. CD3+CD4+ cell infiltrates were detected in the vessel wall samples of these patients. They had a lower mean percentage of Tregs at T0 than controls, but levels increased significantly at T18. Opposite results were found in Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Conclusion: Our data suggest that different pathogenic mechanisms of vessel damage, including atherosclerosis, underlie TAK patients compared with control subjects. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.
ARTICLE | doi:10.20944/preprints201608.0027.v1
Subject: Mathematics & Computer Science, Analysis Keywords: Fuzzy implications; (S,N) implication; residuum t-norm; (T,N) co-implication; residual co-implication
Online: 3 August 2016 (08:29:47 CEST)
Recently, many authors have been interested to introduce fuzzy implications over t-norms and t-conorms. In this paper, we introduce (S,N) and residuum fuzzy implication for Dubois t-norm and Hamacher's t-norm. Also, new concepts so-called (T,N) and residual fuzzy co-implication in dual Heyting Algebra are investigated. Some examples as well as application are discussed as well.
Subject: Biology, Anatomy & Morphology Keywords: T cell receptor; dolphin genome; TRB locus; TRBV; TRBJ; TRBD and TRBC genes; TRA and TRB gene expression analysis; multiple sequence alignments (MSA); 3D modelisation; IMGT
Online: 11 February 2021 (13:26:26 CET)
Bottlenose dolphin (Tursiops truncatus) belongs to the Cetartiodactyla and similarly to the other cetaceans represent the most successful mammalian colonization of the aquatic environment. Here we report a genomic, evolutionary and expression study of Tursiops truncatus T cell receptor beta (TRB) genes. Although the organization of the dolphin TRB locus is similar to that of the other artiodactyl species, with three in tandem D-J-C clusters located at its 3’ end, its uniqueness is given by the reduction of the total length due essentially to the absence of duplications and to the deletions that have drastically reduced the number of the germline TRBV genes. We have analyzed the relevant mature transcripts from two subjects. The simultaneous availability of rearranged TRA and TRB cDNA from the peripheral blood of one of the two specimens, and the human/dolphin amino acids multi sequence alignments, allowed us to calculate the most likely interactions at the protein interface between the alpha/beta heterodimer in complex with major histocompatibility class I (MH1) protein. Interacting amino acids located in the CDR-IMGT of the dolphin variable V alpha and beta domains were identified. According to comparative modelisation, the atome pair contact sites analysis between the human MH1 grove (G) domains and the TR V domains confirms conservation of the structure of the dolphin TR/pMH.
HYPOTHESIS | doi:10.20944/preprints202201.0171.v3
Subject: Medicine & Pharmacology, Oncology & Oncogenics Keywords: ATP; Cancer cell; Cancer Treatment; Mitochondria; T cell
Online: 27 June 2022 (05:07:50 CEST)
Like living organisms, cancer cells require energy to survive and interact with their environment. Mitochondria are the main organelles for energy production and cellular metabolism. Recently, investigators demonstrated that cancer cells can hijack mitochondria from immune cells. This behavior sheds light on a pivotal piece in the cancer puzzle, the ‘dependence’ on the normal cells. This article illustrates the benefits of new, functional mitochondria for cancer cells that urge them to hijack mitochondria. It describes how functional mitochondria help cancer cells’ survival in the harsh tumor microenvironment, immune evasion, progression, and treatment resistance. Recent evidence has put forward the pivotal role of mitochondria in cancer stem cells’ metabolism. This theory highlights the mitochondria in cancer biology and explains how targeted anti-mitochondrial treatments can improve oncological outcomes.
ARTICLE | doi:10.20944/preprints201810.0034.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: T-2 toxin, toxicity, autophagy, apoptosis
Online: 2 October 2018 (16:51:09 CEST)
T-2 toxin produced by fungi of Fusarium genus is highly toxic to human and animals and has been shown to induce apoptosis in various organs/tissues. Apoptosis and autophagy are interconnected processes and these interactions are important for cellular homeostasis as well as pathogenesis. In this study, we report for the first time that T-2 toxin induced autophagy in human liver cells (L02). We showed that T-2 toxin induced the formation of acidic vesicular organelles, concordant with the time and dose-dependent alterations in LC3-phosphatidylethanolamine conjugate (LC3-II) LC3-I/II and p62/SQSTM1 suggesting an enhanced autophagic flux. The T-2 toxin-induced formation of autophagosome and lysosomal fusion was observed by expressing mRFP-GFP-LC3 in L02 cells by lentiviral transduction, and autophagosome was observed by transmission electron microcopy. We found that while T-2 toxin activated both apoptosis and autophagy, activation of autophagy appears to be a leading event reflecting the protective mechanism of cells against the insults by T-2 toxin. Activating autophagy by rapamycin (RAPA) inhibited the apoptosis while suppressing autophagy by chloroquine greatly enhanced the T-2 toxin-induced apoptosis suggesting the crosstalk of autophagy and apoptosis. In summary, our study showed that activation of autophagy protects liver cells from T-2 toxin-induced apoptosis suggesting autophagy may be targeted for prevention of the T-2 toxin-induced toxicity in human and animals.
ARTICLE | doi:10.20944/preprints201804.0354.v1
Online: 27 April 2018 (08:05:09 CEST)
Transient receptor potential vanilloid (TRPV) channels act as sensors of pain, temperature, and other external stimuli. We have recently shown that DPV576, an aqueous mixture of nanodiamond (ND) and nanoplatinum (NP), can modulate the activity of TRPV on human primary keratinocytes, suggesting their potential as a possible pain modulator . CD4+ T lymphocytes also express TRPV channels, and we sought with special interest to examine the effect of DPV576 in modulating the functions of TRPV channel expression and secretion of cytokines on human CD4+ T lymphocytes. Human primary CD4+ T cells were activated with anti CD3/CD28 with and without DPV576 at 1:25 and 1:100 dilutions for 24 hours in vitro. TRPV Receptor expression (TRPV1 and TRPV4) on CD4+ T cells was examined by flow cytometry. The capacity of DPV576 to modulate the activity of TRPV1 agonist capsaicin in CD4+ T cells was also determined. Activation of CD4+ T cells was determined by production of cytokines TNF-α, IFN-γ, and IL-10 using specific ELISA kits. DPV576 treatment of CD4+ T cells that were activated with anti CD3/CD28, resulted in increased expression of TRPV1 channel but had no effect on TRPV4. This was accompanied by increased secretion of IFN-g and reduced expression of TRPV1 in capsaicin activated CD4+ T cells. In addition, DPV576 inhibited the capsaicin, induced the production of both IFN-g and TNF-α, and enhanced the secretion of IL-10. We conclude that short term exposure to DPV576 inhibits the activity of TRPV1 channels in CD4+ T lymphocytes, which may suggest its possible beneficial use for pain management.
REVIEW | doi:10.20944/preprints202010.0514.v1
Subject: Medicine & Pharmacology, Allergology Keywords: Single-Nucleotide Polymorphisms; Point Mutation; Chemokines; T-cells; Viral Infection; Tumorigenesis; T-cell Surface; Immune Response
Online: 26 October 2020 (11:08:40 CET)
C-C Chemokine receptor type 5 (CCR5) is expressed on the CD4 T cell surface where CXCR4 and CCR5 expressions are controlled differently during the activation of T cells and with the binding of interleukin type-2 (IL-2). IL-2 can upregulate CCR1 and CCR2 in CD45R01 T cells and increase the T lymphocyte chemotaxis toward CC-chemokines. CD4+ T cells are either apart of the T helper 1 or Th1 lymphocytes that release interferon gamma (IFNγ) and lymphotoxin that provide cellular immunity to internal pathogens and T helper cells type 2 (Th2), which secrete interleukins 4 and 5 (IL-4 and IL-5). IL-4 and IL-5 cause an allergic and humoral immune response to parasites. Th2 lymphocytes use CCR3 chemokine receptors. CCR5 and CXCR3 chemokine receptors are specific for CD4+ Th1 and Th2 lymphocytes. CCR5Δ32 is a 32-base-pair deletion of the CCR5 gene. CCR5 is a co-receptor for the entrance of the human immunodeficiency virus-1 (HIV-1). CCR5Δ32 creates a malfunction of the CCR5 protein that can prevent HIV-1 infection. However, the CCR5Δ32 32-base-pair deletion is not prevalent and predominant in many populations worldwide and there also exist more genetic variations of CCR5 known as CCR5-SNPs. An alternative polymorphism was identified based on the CCR5 gene that was identified as a A to G (A/G) point mutation. This point mutation is located at the 59029 locus on the promoter that lowers the expression rate of CCR5. Gurdol et al. found activity at the promoter of CCR5/590029G was 45% lesser than the CCR5/59029A. The genetic variations of CCR5 SNPs also include: 2459G>SNP of CCR5, C101X, CCR5 gene position at -2273, and the A to G SNP mutation found in two South African blacks. Therefore, more studies are needed to find more and varied chemokine polymorphisms that are present in many diverse populations in the world. The aim of this literature review is to describe the immense impact of CCR5 SNP mutations on viral infection susceptibility, on the pathogenesis of chronic conditions, to endorse the increased discovery of more novel CCR5 SNPs, and to show the significant potential of anti-CCR5 therapies to treat multiple diseased conditions.
ARTICLE | doi:10.20944/preprints202209.0275.v1
Subject: Engineering, Civil Engineering Keywords: Bicycle Behavior; Naturalistic Cycling Data; Car/Bike Interactions; Computer Vision; Object Detection
Online: 19 September 2022 (10:22:00 CEST)
As machine learning and computer vision techniques and methods continue to advance, the collection of naturalistic traffic data from video feeds is becoming more and more feasible. That is especially true for the case of bicycles, for which the collection of naturalistic data is not achievable in the traditional vehicle approach. This study describes a research effort that aims to extract naturalistic cycling data from a video dataset for use in safety and mobility applications. The used videos come from a dataset collected in a previous Virginia Tech Transportation Institute study in collaboration with SPIN in which continuous video data at a non-signalized intersection on the Virginia Tech campus was recorded. The research team applied computer vision and machine learning techniques to develop a comprehensive framework for the extraction of naturalistic cycling trajectories. In total, this study resulted in the collection and classification of 619 bicycle trajectories based on their type of interactions with other road users. The results confirm the success of the proposed methodology in relation to extracting the locations, speeds, and accelerations of the bicycles at a high level of precision. Furthermore, preliminary insights into the acceleration and speed behavior of bicyclists around motorists are determined.
ARTICLE | doi:10.20944/preprints202012.0074.v1
Subject: Life Sciences, Biochemistry Keywords: maternal vaccination; autogenous inactivated vaccine; transfer of immunity; humoral immune response; cell-mediated immune response; T cells; PRRSV; swine; IFN-γ producing B cells; CD4 TEMRA cells
Online: 3 December 2020 (09:02:58 CET)
Maternal-derived immunity is a critical component for survival and success of offspring in pigs to protect from circulating pathogens like Type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-2). The purpose of this study was to investigate the transfer of anti-PRRSV immunity to piglets from gilts that received modified-live virus (MLV) alone (TRT 0), or in combination with one of two autogenous inactivated vaccines (AIVs, TRT 1+2). Piglets from these gilts were challenged with the autogenous PRRSV-2 strain at two weeks of age and their adaptive immune response (IR) was evaluated until 4 weeks post inoculation (wpi). The systemic humoral and cellular IR was analyzed in the pre-farrow gilts, and in piglets, pre-inoculation, and at 2- and 4-wpi. Both AIVs partially protected the piglets with reduced lung pathology and increased weight gain; TRT 1 also lowered piglet viremia best explained by the AIV-induced production of neutralizing antibodies in gilts and their transfer to the piglets. In piglets, pre-inoculation, the main systemic IFN-γ producers were CD21α+ B cells. From 0 to 4 wpi, the role of these B cells declined and CD4 T cells became the primary systemic IFN-γ producers. In lungs, CD8 T cells were the primary and CD4 T cells the secondary IFN-γ producers including a novel subset of porcine CD8α-CCR7- CD4 T cells, potentially terminally differentiated CD4 TEMRA cells. In summary, this study demonstrates that maternal AIV vaccination can improve protection of pre-weaning piglets against PRRSV-2; it shows the importance of transferring neutralizing antibodies to piglets; and it introduces two novel immune cell subsets in pigs – IFN-γ producing CD21α+ B cells and CD8α-CCR7- CD4 T cells.
REVIEW | doi:10.20944/preprints202103.0138.v1
Online: 3 March 2021 (14:54:03 CET)
For several years, drugs bearing reactive electrophilic appendages have been developed. These units typically confer prolonged residence time of the drugs on their protein targets, and may assist targeting shallow binding sites and/or improving drug-protein target spectrum. Studies on natural electrophilic molecules have indicated that in many instances natural electrophiles use similar mechanisms to alter signaling pathways. However, natural reactive species are also endowed with other important mechanisms to hone signaling properties that are uncommon in drug design. These include ability to be active at low occupancy and elevated inhibitor kinetics. Here we discuss how we have begun to harness these properties in inhibitor design.
ARTICLE | doi:10.20944/preprints201811.0360.v1
Online: 15 November 2018 (11:13:55 CET)
The study was done to determine the effect of supplementing different forms of L-methionine (L-Met) and acetate on protein synthesis in immortalized bovine mammary epithelial cell line (MAC-T Cell): Control, L-Met, conjugated L-Met and acetate (CMA), and non-conjugated L-Met and Acetate (NMA). Protein synthesis mechanism was determined by omics method. NMA group had the highest protein content in the media and β-casein mRNA expression levels (P < 0.05). The number of upregulated and downregulated proteins observed were 77 and 62 in CMA group and 50 and 81 in NMA group from 448 proteins, respectively (P < 0.05). NMA and CMA treatments stimulated pathways related to protein and energy metabolism (P < 0.05). Metabolomic analysis also revealed CMA and NMA treatments resulted in increases of several metabolites (P < 0.05). In conclusion, NMA treatment increased protein concentration and expression level of β-casein mRNA in MAC-T cells compared to CMA.
ARTICLE | doi:10.20944/preprints201805.0287.v1
Online: 22 May 2018 (05:47:25 CEST)
The article presents tests aimed to verify the possibility of making T-joints in TMCP steel using laser. The tests involved the use of 10 mm thick high yield point steel S700MC obtained in an industrial manufacturing process. The joints made in the tests were single and double-sided. Subsequent non-destructive tests revealed that the joints obtained in the tests represented quality level B in accordance with PN-EN ISO 13919-1. Single-sided welding performed using the laser beam having a power of 11 kW enabled the obtainment of 8 mm deep penetration without visibly deforming the web of the joint. The double-sided welded joints were characterised by proper geometry and the presence of gas pores in the welds not compromising the requirements of quality level B (strict requirements). The weld structure was bainitic-ferritic. The weld hardness was by approximately 60 HV1 higher than that of the base material (280 HV1). The HAZ area was slightly softer than the base material. The tests of thin foils performed using a high-resolution scanning transmission electron microscope revealed that, during welding, an increase in the content of the base material in the weld was accompanied by an increase in contents of alloying microagents Ti and Nb, particularly near the fusion line. The above-named alloying microagents, in the form of fine-dispersive (Ti,Nb)(C,N) type precipitates, could reduce plastic properties of joints.
ARTICLE | doi:10.20944/preprints201808.0030.v1
Subject: Life Sciences, Virology Keywords: Dengue virus; Zika virus; T-cell epitopes; cross-reactive T cells; immunodominance; neutralizing antibodies; antibody-dependent-enhancement (ADE)
Online: 2 August 2018 (05:04:43 CEST)
The high level of dengue virus (DENV) seroprevalence in areas where Zika virus (ZIKV) is circulating and the cross-reactivity between these two viruses have raised concerns on the risk of increased ZIKV disease severity for patients with a history of previous DENV infection. To determine the role of DENV pre-immunity in ZIKV infection, we analysed the T and B cell responses against ZIKV in donors with or without previous DENV infection. Using PBMCs from donors living in an endemic area in Colombia, we have identified, by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay, most of the immunodominant ZIKV T-cell epitopes in the non-structural proteins NS1, NS3 and NS5. Analyses of the T and B-cell responses in the same donors revealed a stronger T-cell response against peptides conserved between DENV and ZIKV, with a higher level of ZIKV-neutralizing antibodies in DENV-immune donors, in comparison with DENV-naïve donors. Strikingly, the potential for antibody mediated enhancement of ZIKV infection was reduced in donors with sequential DENV and ZIKV infection in comparison with donors with DENV infection only. Altogether, these data suggest that individuals with DENV immunity present improved immune responses against ZIKV.
ARTICLE | doi:10.20944/preprints201804.0293.v1
Subject: Mathematics & Computer Science, Algebra & Number Theory Keywords: double framed T-soft fuzzy set; double framed T-soft fuzzy algebra; double framed B-soft fuzzy algebra
Online: 23 April 2018 (12:15:40 CEST)
The aim of this article is introduced the concept of double framed T-soft fuzzy set (DFT-soft fuzzy set) which is the combination of soft set and fuzzy set. We also defined the notions and apply this concept in BCK/BCI-algebras. By using example, we also discussed the concept of double framed T-soft fuzzy algebra (DFT-soft fuzzy algebra) and double framed B-soft fuzzy algebra (DFB-soft fuzzy algebra) and also investigated their properties. Each double framed T-soft fuzzy algebra is double framed B-soft fuzzy algebra but by using example, we proved that converse may or may not be possible.
ARTICLE | doi:10.20944/preprints202203.0411.v1
Subject: Medicine & Pharmacology, Other Keywords: COVID-19; SARS-CoV-2; Vaccines; anti-SARS-CoV-2 spike total antibodies; Surrogate viral neutralizing antibody; T-cell immune response; CoronaVac; ChAdOx1; BNT162b2; booster
Online: 31 March 2022 (14:28:11 CEST)
Inactivated SARS-CoV-2 vaccine (CoronaVac) is commonly used in national immunization programs. However, the immune response significantly declined within a few months. Our study assessed the immune response against SARS-CoV-2 after receiving booster shots of BNT162b2 or ChAdOx1 among health care workers who previously received CoronaVac as their primary immunization. Fifty-six participants received ChAdOx1 and forty-two participants received BNT162b2 were enrolled into this study which evaluated the immune responses including anti-SARS-CoV-2 spike total antibodies (Elecsys®), surrogated viral neutralization test (sVNT) to ancestral strain (cPass™; GenScript) and five variants of concern (Alpha, Beta, Gamma, Delta, and Omicron) (Luminex; multiplex sVNT) and the ELISpot with spike (S1 and S2) peptide pool against the ancestral SARS-CoV-2 strain. The samples were analyzed at baseline, 4, and 12 weeks after primary immunization as well as 4 and 12 weeks after receiving the booster. This study showed a significantly higher B-cell response among the BNT162b2 than the ChAdOx1 booster group, particularly against the Omicron variant, as well as a trend of good T-cell immune response in the BNT162b2 group. Moreover, the immune response rapidly declined at 12 weeks after the booster. A fourth dose or a second booster should be recommended, especially for reducing Omicron severity.
ARTICLE | doi:10.20944/preprints202206.0311.v1
Subject: Mathematics & Computer Science, Analysis Keywords: t-norms; fuzzy seminorm; Minkowski functional; fuzzy topology
Online: 22 June 2022 (08:47:09 CEST)
In this paper, the concept of fuzzy locally convex spaces generated by a family of fuzzy seminorms is introduced. We prove that a Minkowski functional of zero neighborhoods generates a seminorm and finally deduce that the topology generated by the family of seminorms coincides with that of the Minkowski functional.
REVIEW | doi:10.20944/preprints202104.0680.v1
Subject: Life Sciences, Biochemistry Keywords: P. falciparum; T. gondii; upstream ORFs; translational regulation
Online: 26 April 2021 (15:11:40 CEST)
During their complex life cycles, the Apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii employ several genetic switches to regulate their gene expression. One such switch is mediated at the level of translation through upstream Open Reading Frames (uORFs). As uORFs are found in the upstream regions of a majority of genes in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant proteins that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics, and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of genome-wide datasets will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response, and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.
REVIEW | doi:10.20944/preprints202101.0617.v1
Subject: Materials Science, Biomaterials Keywords: zeolite T; offretite; erionite; hydrothermal; microwave; secondary growth
Online: 29 January 2021 (12:34:58 CET)
Synthesis of zeolite T with a variety of desired characteristics necessitate extensive work in the formulation and practical experiments either by conventional hydrothermal methods or aided with different approaches and synthesis techniques such as secondary growth or microwave irradiation. The objectives of this review are to adduce the potential work in zeolite T (Offretite-Erionite) synthesis evaluating determining factors affecting the synthesis and quality of the zeolite T crystals. Attention is given to the extensive studies that interconnect with other significant findings.
ARTICLE | doi:10.20944/preprints202101.0435.v1
Subject: Engineering, Electrical & Electronic Engineering Keywords: QoS; QoE; ITU-T; TRV; P.912; CCTV
Online: 22 January 2021 (08:43:35 CET)
It was once thought that high QoS (Quality of Service) performance solves recurrent problems of low-quality multimedia services. Since then, solutions have been proposed to ensure a high level of QoE (Quality of Experience). In this document, the authors attempt to outline their understanding of an accurate meaning of quality of multimedia services. Starting from QoS and passing through generalised QoE, the authors focus on aspects of subjective and objective quality modelling and optimisation of visual performance for TRV (Target Recognition Video) applications (such as video surveillance), outlining the path of ITU-T standardisation in this area. The authors revised the ITU-T Recommendation P.912 to reflect improved subjective test techniques developed since this Recommendation was approved. The authors also attempt to predict at least some existing errors of reasoning, which are likely to become evident for the industry in the next decade.
REVIEW | doi:10.20944/preprints201807.0304.v1
Subject: Life Sciences, Immunology Keywords: IBD; CCR6; CCL20; Immune mechanisms; T helper lymphocytes
Online: 17 July 2018 (10:37:41 CEST)
Inflammatory bowel disease (IBD) has evoked a significant interest in human immunobiology given its tactical immune evasion methodologies resulting in acute immune destabilization. IBD comprising of Crohn’s disease and Ulcerative colitis manifest as chronic inflammation in the gut mucosa, leading to complexities involving immune dysregulation in the T helper lymphocyte arm effecting disease pathogenicity. The mucosa of the alimentary canal is constantly exposed to a myriad of food antigens and luminal microorganisms for which a consistent host-protective mechanism is operative in healthy people. Lowered mucosal immune expression which allows penetration of the epithelial barrier by infective pathogenic microbes, elicits both innate and adaptive immune responses in the gut culminating in aberrant intestinal inflammation. Interestingly, IBD leukocyte repertoire is significantly entwined with chemokine assisted chemotactic navigation into the sites of inflammation which is also thought to generate favourable immune suppressive responses. The functions of the cognate chemokine receptor, CCR6, which binds with its unique ligand CCL20, are expected to tilt the balance between upregulation of homeostatic tolerance and inflammatory pathophysiology. This review aims at critically examining the CCR6 driven immune pathways; TH1/TH2, TH1/TH17, TH17/ Treg, IL-23/IL-17, Akt/ERK-1 /2, ILC3 for systematic investigation of its underlying mechanisms in the future and to underpin its importance in resolving IBD aetiopathology. Thus, CCR6 occupies an exclusive position in gut immunology which renders it an invaluable therapeutic tool for the production of novel medicaments to treat IBD.
ARTICLE | doi:10.20944/preprints202106.0459.v1
Subject: Engineering, Automotive Engineering Keywords: Autonomous Driving System; In-Car Gaming; Driver Behavior; Driving Related Tasks; 3D-VR/AR
Online: 17 June 2021 (12:29:00 CEST)
As Automated Driving Systems (ADS) technology gets assimilated into the market, the driver’s obligation will be changed to a supervisory role. A key point to consider is the driver’s engagement in the secondary task to maintain the driver/user in the control loop. The paper’s objective is to monitor driver engagement with a game and identify any impacts the task has on hazard recognition. We designed a driving simulation using Unity3D and incorporated three tasks: No-task, AR-Video, and AR-Game tasks. The driver engaged in an AR object interception game while monitoring the road for threatening road scenarios. From the results, there was less than 1 second difference between the means of gaming task (mean = 2.55s, std = 0.1002s) to no-task (mean = 2.55s, std = 0.1002s). Game scoring followed three profiles/phases: learning, saturation, and decline profile. From the profiles, it is possible to quantify/infer drivers’ engagement with the game task. The paper proposes alternative monitoring that has utility, i.e., entertaining the user. Further experiments AR-Game focusing on real-world car environment will be performed to confirm the performance following the recommendations derived from the current test.
REVIEW | doi:10.20944/preprints201807.0237.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: TRPM7, kinase, inflammation, lymphocytes, calcium signalling, SMAD, TH17, hypersensitivity, regulatory T cells, thrombosis, graft versus host disease, T cells, innate immunity
Online: 13 July 2018 (14:14:56 CEST)
The enzyme-coupled transient receptor potential channel subfamily M member 7, TRPM7, has been associated with immunity and immune cell signalling. Here, we review the role of this remarkable signalling protein in lymphocyte proliferation, differentiation, activation and survival. We also discuss its role in mast cell, neutrophil and macrophage function and highlight the potential of TRPM7 to regulate immune system homeostasis. Further, we shed light on how the cellular signalling cascades involving TRPM7 channel and/or kinase activity culminate in pathologies as diverse as allergic hypersensitivity, arterial thrombosis, and graft versus host disease (GVHD), stressing the need for TRPM7 specific pharmacological modulators.
REVIEW | doi:10.20944/preprints202207.0001.v1
Subject: Life Sciences, Immunology Keywords: autoimmunity; T-Cell; LncRNAs; miRNAs; RA; T1D; MS; SLE
Online: 1 July 2022 (03:49:07 CEST)
The importance of a properly regulated immune response has been explored through various research-oriented methods. It has proved that having an effective and well-regulated immune response helps prevent many minors and serious diseases. Any kind of dysregulation in the working of the immune system may lead to severe consequences. An autoimmune disorder is one such consequence in which the component of the immune system starts targeting self-cells of the body, treating them as self-antigen producing autoantibodies and immune complexes resulting from the failure of immune responses both at a central and peripheral level. Currently, many autoimmune disorders are prevailing across the world, and new diseases need attention.In this review, we have written about the functions of T cell, LncRNAs and also some interactions between the LncRNAs and miRNAs in the pathogenesis of Multiple sclerosis (MS), Systemic lupus erythematosus (SLE), Type 1 diabetes (T1D), Rheumatoid arthritis (RA). To find the functions of these autoimmune disorders we have done intensive literature search during this we also found that GAS5 and MALAT are common in MS, SLE, T1D, RA. And finally, we have also mentioned the therapeutic drugs which neutralizes the different cluster of differentiation (CDs) and also suppresses the T cell differentiation in MS, SLE and RA. For T1D therapeutic strategies and various types of insulin are mentioned.
REVIEW | doi:10.20944/preprints202201.0440.v1
Subject: Life Sciences, Other Keywords: electrophiles; signaling; profiling; drug mechanism; drug discovery; T-REX
Online: 28 January 2022 (14:57:08 CET)
Our bodies produce a host of electrophilic species that can label specific endogenous proteins in cells. The signaling roles of these molecules are underactive debate. However, in our opinion it is becoming increasingly likely that electrophiles can rewire cellular signaling processes at endogenous levels. Attention is turning more to understanding how nuanced electrophile signaling in cells is. In this perspective, we describe recent work from our laboratory that has started to inform on different levels of context-specific regulation of proteins by electrophiles. We discuss the relevance of these data to the field, and to the broader application of electrophile signaling to precision medicine development, beyond the traditional views of their pleiotropic cytotoxic roles.
REVIEW | doi:10.20944/preprints202108.0387.v1
Online: 18 August 2021 (14:21:46 CEST)
Novel Cellular Immunotherapy with engineered T cells has improved cancer treatment and established therapeutic promises to prevent tumor formation in clinical studies. Due to certain restrictions and difficulties, CAR and TCR T cells therapies were inadequate at points. CRISPR Cas9 genome-editing tool has a significant potential for these two cell-based therapies. As a specialized gene-editing technique, CRISPR Cas9 is used to repair genetic alternation with minimum damage. It is used as an adjunct to Immunotherapy to stimulate a more robust immune response. CRISPR has long outpaced other target-specific genome editing methods such as ZFNs and TALEN due to its high efficiency, competence in targeting, and stable operating condition. CRISPR can overcome the two major drawbacks of universal CAR T cells: allorejection and graft-vs-host disease. TCR-based T cell treatment can reduce inappropriate binding between endogenous and transgenic TCR, resulting in a reduction of severe toxicity. The CAR and TCR T based cell therapies uphold an excellent future for tumor malignancies This article has elucidated the administration of CRISPR Cas9 in Novel Cellular Immunotherapy, CAR, and TCR T cell therapy. However, this article did not fail to observe this technology's ethical concerns, limitations, and challenges. Furthermore, the article compares CRISPR-mediated allogeneic CAR T cell to TCR-T cell therapy.
ARTICLE | doi:10.20944/preprints202104.0072.v1
Subject: Life Sciences, Biochemistry Keywords: T cells; protein immunodominance; cytokine polarization; influenza viruses; vaccine
Online: 2 April 2021 (14:28:32 CEST)
The role of T cell immunity has been acknowledged in recent vaccine development and evaluation. We tested the humoral and cellular immune responses to Flucelvax®, a quadrivalent inactivated seasonal influenza vaccine containing two influenza A (H1N1 Singapore/GP1908/2015 IVR-180 and H3N2 North Carolina/04/2016) and two influenza B (Iowa/06/2017 and Singapore/INFTT-16-0610/2016) virus strains, using peripheral blood mononuclear cells stimulated by pools of peptides overlapping all the individual influenza viral protein components. Baseline reactivity was detected against all four strains both at the level of CD4 and CD8 responses and targeting different proteins. CD4 T cell reactivity was mostly directed to HA/NA proteins in influenza B strains, and NP/M1/M2/NS1/NEP proteins in the case of the Influenza A strains. CD8 responses to both influenza A and B viruses preferentially targeted the more conserved core viral proteins. Following vaccination, both CD4 and CD8 responses against the various influenza antigens were increased in day 15 to day 91 post vaccination period and maintained a Th1 polarized profile. Importantly, no vaccine interference was detected, with the increased responses balanced across all 4 included viral strains for both CD4 and CD8 T cells, and targeting HA and multiple additional viral antigens.
REVIEW | doi:10.20944/preprints202008.0500.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: Alzheimer; blood brain barrier; CD4+ T cells; migration; medication
Online: 24 August 2020 (03:08:41 CEST)
The effect of Alzheimer's disease (AD) medications on CD4+ T cells homing has not been thoroughly investigated. Alzheimer's disturbs the life of at least five million persons in the USA. CD4+ T cells could both exacerbate and reduce AD symptoms. Regulating CD4+ T cells homing to the leaky blood-brain barrier (BBB) constitutes a new hope for enhancing AD prognosis. Alzheimer's drugs such as Donepezil (Aricept), Rivastigmine (Exelon), Galantamine (Razadyne) and memantine are known to play an important part in regulating the neurotransmitters mechanisms. However, little is known about the effect of these drugs on CD4+ T cells homing. In this review, we focus on current and new drugs that could modulate CD4+ T cells interactions with the BBB in AD.
ARTICLE | doi:10.20944/preprints202006.0094.v1
Subject: Medicine & Pharmacology, General Medical Research Keywords: CCCP; Mitophagy; Regulatory T cells; Flow cytometry; fluorescence microscopy
Online: 7 June 2020 (15:03:23 CEST)
Objective: To investigate the effects and mechanisms of different concentrations of CCCP on mitophagy in human peripheral blood regulatory T cells. Methods: Tregs were isolated, identified and then grouped, treating with CCCP at a concentration of 2.5 μM, 5 μM, 10 μM, 20 μM and 40 μM for 24h in an incubator. Flow cytometry detected the reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial quality, and fluorescence microscopy observed the co-localization of mitochondria and lysosomes in each group. Results: The purity of CD4+CD25+Tregs was (93.36 ± 1.87) %. With the increase of CCCP concentration, the level of ROS gradually increased, while the MMP decreased gradually. About the mitochondria and lysosome fusion, the fluorescence intensity of orange (yellow) was the highest when the concentration of CCCP was in the range of 5-10 μM while decreased with the CCCP concentration continually increasing. The mitochondrial quality decreased with the increase of CCCP concentration. However, there was no significant difference between groups C, D and E. The mitochondrial quality of groups F and G were significantly lower than that of group E. Conclusions: With the concentration of CCCP gradually increased, the level of ROS in Treg cells increased, and MMP decreased, which promoted the mitophagy, mitochondrial quality maintains homeostasis; When ROS accumulated, and MMP decreased significantly, the mitophagy was inhibited, and the mitochondrial quality was significantly decreased.
BRIEF REPORT | doi:10.20944/preprints202002.0167.v1
Online: 13 February 2020 (10:53:40 CET)
The outbreak of the 2019 Novel Coronavirus (2019-nCoV) has rapidly spread from Wuhan, China to multiple countries, causing staggering number of infections and deaths. A systematic profiling of the immune vulnerability landscape of 2019-nCoV is lacking, which can bring critical insights into the immune clearance mechanism, peptide vaccine development, and antiviral antibody development. In this study, we predicted the potential of all the 2019-nCoV viral proteins to induce class I and II MHC presentation and form linear antibody epitopes. We showed that the enrichment for T cell and B cell epitopes is not uniform on the viral genome, with several focused regions that generate abundant epitopes and may be more targetable. We showed that genetic variations in 2019-nCoV, though fewer for the moment, already follow the pattern of mutations in related coronaviruses, and could alter the immune vulnerability landscape of this virus, which should be considered in the development of therapies. We create an online database to broadly share our research outcome. Overall, we present an immunological resource for 2019-nCoV that could significantly promote both therapeutic development and mechanistic research.
ARTICLE | doi:10.20944/preprints201910.0306.v1
Subject: Engineering, Mechanical Engineering Keywords: T-shaped microchannel; degree of mixing; twisting angle; optimization
Online: 27 October 2019 (11:11:58 CET)
A new design scheme is proposed for twisting the walls of a microchannel, and its performance is demonstrated numerically. The numerical study was carried out for a T-shaped microchannel with twist angles in the range of 0 to 34π. The Reynolds number range was 0.15 to 6. The T-shaped microchannel consists of two inlet branches and an outlet branch. The mixing performance was analyzed in terms of the degree of mixing and relative mixing cost. All numerical results show that the twisting scheme is an effective way to enhance the mixing in a T-shaped microchannel. The mixing enhancement is realized by the swirling of two fluids in the cross section and is more prominent as the Reynolds number decreases. The twist angle was optimized to maximize the DOM, which increases with the length of the outlet branch. The twist angle was also optimized in terms of the relative mixing. The two optimum twisting angles are generally not coincident. The optimum twist angle shows a dependence on the length of the outlet branch but it is not affected much by the Reynolds number.
ARTICLE | doi:10.20944/preprints201812.0110.v1
Subject: Social Sciences, Sociology Keywords: Philosophy, Education, Booker T. Washington, W.E.B. Du Bois, Vocationalism
Online: 10 December 2018 (15:38:28 CET)
This paper explores the rationale behind Booker T. Washington’s vocationalist philosophy of education for the then recently emancipated black population. Through the use of a critical thinking framework, an analysis of remarks from key speeches and his life according to scholars providing Washington’s prescriptive argument and rhetoric is undertaken. Despite Washington’s intentions, the argument for his vocational approach is demonstrated to be oppressive, myopic, and circular in its logic. The author proposes a framework for understanding the counterintuitive development of vocationalist philosophy based on the dichotomous nature of the human experience’s value-construct and context misalignment. Concordant or discordant dualities that result from misalignment are explained and how to reconcile Washington’s Vocationalism with opposing the philosophy of W.E.B. Du Bois due to equivalence or consistency of values with theoretical constructs is also discussed.
ARTICLE | doi:10.20944/preprints202102.0155.v1
Subject: Engineering, Automotive Engineering Keywords: Direct Yaw Moment Control; Electric Race Car; FSAE; Limit Handling; Yaw Rate Control; Lap Time Simulation
Online: 5 February 2021 (10:34:02 CET)
Direct yaw moment control (DYC) is an effective way to alter the behaviour of electric cars with independent drives. Controlling the torque applied to each wheel can improve the handling performance of a vehicle making it safer andfaster on a race track. The state-of-the-art literature covers the comparison of various controllers (PID, LPV, LQR, SMC, etc.) using ISO manoeuvres. However, more advanced comparison on important characteristics of the controllers performance is missed, such as the robustness of the controllers under changes in the vehicle model, steering behaviour, use of the friction circle and, ultimately, lap time on a track. In this study, we have compared the controllers according to some of the aforementioned parameters on a modelled race car. Interestingly, best lap times are not provided by perfect neutral or close-to-neutral behaviour of the vehicle, but rather by allowing certain deviations from the target yaw rate. In addition, a modified PID controller showed that its performance is comparable to other more complex control techniques such as MPC.
ARTICLE | doi:10.20944/preprints202007.0332.v1
Subject: Chemistry, General & Theoretical Chemistry Keywords: Car-Parrinello molecular dynamics; ab-initio molecular dynamics; sum-frequency generation spectroscopy; maximally localized Wannier orbitals
Online: 15 July 2020 (10:25:31 CEST)
In the present work, we provide an electronic structure based method for the “on-the-fly” deter- mination of vibrational sum frequency generation (v-SFG) spectra. The predictive power of this scheme is demonstrated at the air-water interface. While the instantaneous fluctuations in dipole moment are obtained using the maximally localized Wannier functions, the fluctuations in polar- izability are approximated to be proportional to the second moment of Wannier functions. The spectrum henceforth obtained captures the signatures of hydrogen bond stretching, bending, as well as low-frequency librational modes.
Subject: Life Sciences, Immunology Keywords: allergy; regulatory T cells; IL-2; IL-4; Th2; tolerance
Online: 25 May 2022 (09:45:52 CEST)
This manuscript provides a new integrated view of the development of allergen-specific TH2 and the lack of their associated Treg cells in a unified model, justifying the need for IL-2 to correct allergy conditions.
ARTICLE | doi:10.20944/preprints202202.0081.v1
Subject: Mathematics & Computer Science, Probability And Statistics Keywords: Online learning; Anomaly detection; Hotelling’s T-squared test; Digital phenotyping
Online: 7 February 2022 (11:54:54 CET)
To detect aberrant human behaviors from large volume of passive data collected by smartphones in real time, we propose an online anomaly detection method using Hotelling’s T-squared test. The test statistic is a weighted average, with more weight on the between-individual component when there are little data available for the individual and more weight on the within-individual component when the data are adequate. The algorithm takes only O(1) run time in each update and the required memory usage is fixed after a pre-specified number of updates. The performance of the proposed method, in terms of accuracy, sensitivity and specificity, is consistently better than or equal to the offline method that it builds upon depending on the sample size of the individual data.
ARTICLE | doi:10.20944/preprints202109.0454.v1
Subject: Life Sciences, Molecular Biology Keywords: CPA4; Bladder Urothelial Carcinoma; Immune cells; T cell exhaustion; checkpoint
Online: 27 September 2021 (16:02:31 CEST)
Carboxypeptidase A4 (CPA4) has shown the potential possibility as a biomarker in the early diagnosis for certain cancers. However, no previous research has linked CPA4 to therapeutic or prognostic significance in bladder cancer. Using data from The Cancer Genome Atlas (TCGA) database, we set out to determine the full extent of the link between CPA4 and BLCA. We further analyzed the interacting proteins of CPA4 and infiltrated immune cells via TIMER2，STRING and GEPIA2 databases. The expression of CPA4 in tumor and normal tissues was compared using the TCGA+GETx database. The connection between CPA44 expression and clinicopathologic characteristics and overall survival (OS) was investigated using multivariate methods and Kaplan-Meier survival curves. The potential functions and pathways were investigated via gene set enrichment analysis. Furthermore, we analyze the associations between CPA4 expression and infiltrated immune cells with their respective gene marker sets using the ssGSEA, TIMER2, and GEPIA2 databases. Compared to matching normal tissues, human CPA4 was found to be substantially expressed. We confirmed that overexpression of CPA4 is linked with shorter OS, DSF, PFI, and increased diagnostic potential using Kaplan-Meier and ROC analysis. The expression of CPA4 is related to T-bet, IL12RB2, CTLA4, and LAG3, among which T-bet and IL12RB2 are Th1 marker genes, while CTLA4 and LAG3 are related to T cell exhaustion, which may be used to guide the application of checkpoint blockade and the adoption of T cell transfer therapy.
REVIEW | doi:10.20944/preprints202108.0406.v1
Subject: Life Sciences, Biotechnology Keywords: superantigen; T-cell; B-cell; cytokine storm; interface; antibody purification
Online: 19 August 2021 (19:25:42 CEST)
Superantigens are unconventional antigens which recognise immune receptors outside the usual binding sites e.g. complementary determining regions (CDRs), to elicit a response within the target cell. T-cell superantigens crosslink T-cell receptors and MHC Class II molecules on antigen-presenting cells, leading to lymphocyte recruitment, induction of cytokine storms and T-cell anergy or apoptosis among many other effects. B-cell superantigens, on the other hand, bind immunoglobulin receptors on B-cells affecting opsonisation, IgG-mediated phagocytosis, and drive B-cells into apoptosis. Here, through a review of the structural basis for recognition of immune receptors by superantigens, we show that their binding interfaces share specific physicochemical characteristics when compared with other protein-protein interaction complexes. Given that antibody-binding superantigens have been exploited extensively in industrial antibody purification, these observations could facilitate further protein engineering to optimize the use of superantigens in this and other areas of biotechnology.
Subject: Life Sciences, Biochemistry Keywords: food allergy; IgE; memory responses; anaphylaxis; B cells; T cells;
Online: 5 May 2021 (12:38:46 CEST)
Recent evidence has highlighted the critical role of memory cells in maintaining lifelong food allergies, thereby identifying these cells as therapeutic targets. IgG+ memory B cells replenish pools of IgE-secreting cells upon allergen exposure, which contract thereafter due to the short lifespan of tightly regulated IgE-expressing cells. Advances in the detection and highly dimensional analysis of allergen-specific B and T cells from allergic patients have provided insight on their phenotype and function. The newly identified Th2A and Tfh13 populations represent a leap in our understanding of allergen-specific T cell phenotypes, though how these populations contribute to IgE memory responses remains poorly understood. Within, we discuss the mechanisms by which memory B and T cells are activated, integrating knowledge from human systems and fundamental research. We then focus on memory reactivation; specifically, on the pathways of secondary IgE responses. Throughout, we identify areas of future research which will help identify immunotargets for a transformative therapy for food allergy.
ARTICLE | doi:10.20944/preprints202008.0717.v1
Subject: Biology, Physiology Keywords: erythrocytes; microvesicles; oxidative stress; band 3; t-BOOH; A23187; SNC
Online: 31 August 2020 (09:40:04 CEST)
Extracellular vesicles (EVs) released by different cell types play significant role in many physiological and pathophysiological processes. In physiological conditions red blood cells (RBCs) derived EVs compose 4 - 8% of all circulating EVs, and oxidative stress (OS) as a consequence of different pathophysiological conditions significantly increases the amount of circulated RBC-derived EVs, however the mechanisms of EV formation are not fully defined yet. To analyze OS-induced EV formation and RBCs transformations we used flow cytometry to evaluate cell esterase activity, caspase-3 activity, and band 3 clustering. Band 3 clustering was additionally analyzed by confocal microscopy. Two original laser diffraction-based approaches were used for analysis of cell deformability and band 3 activity. Hemoglobin species were characterized spectrophotometrically. We showed that cell viability in tert-butyl hydroperoxide-induced OS directly correlated with oxidant concentration to cell count ratio, RBCs-derived EVs contained hemoglobin oxidized to hemichrome (HbChr). OS induced caspase-3 activation and band 3 clustering in cells and EVs. Importantly, we showed that OS-induced EV formation is independent from calcium. Presented data indicated that during OS RBCs eliminate HbChr by vesiculation, in order to sacrifice the cell itself thereby prolonging lifespan and delaying the untimely clearance of in all other respects healthy RBCs.
TECHNICAL NOTE | doi:10.20944/preprints202008.0467.v1
Subject: Life Sciences, Immunology Keywords: HLA diversity; HLA frequency; predicted T-cell epitopes; immunogenic breath
Online: 21 August 2020 (03:39:15 CEST)
Existing approaches to identifying predictive T-cell epitopes have traditionally utilized either 2-digit HLA super-families or more commonly autologous HLA alleles to facilitate the predictions, but frequently they may not consider their representation within a population. Here we propose a modification to this concept whereby subsets of individuals are selected for their specific HLA allele profiles and the representation they provide within a given population. Using this targeted approach to HLA selection and the linkages to specific individuals may enable the design of restricted experimental strategies.
HYPOTHESIS | doi:10.20944/preprints202006.0038.v1
Subject: Keywords: T-lymphocytes; programmed cell death protein-1; mitochondria; adenosine triphosphate
Online: 4 June 2020 (13:54:40 CEST)
It has been demonstrated that a decrease in cellular adenosine triphosphate (c-ATP) causes cellular dysfunction. T-cells are not an exception. One of their roles is to properly detect and eliminate cancer cells. These processes occur at the expense of ATP. Therefore, it can be concluded that a decrease in c-ATP can defect T-cell function and promote cancer evolution. In this article, we provide a hypothesis to describe the correlation between the expression of PD-1 protein on T-cells and their c-ATP levels. Moreover, we present the possible predictive factors of Anti–PD(L)-1 therapy which has not yet been determined definitely.